Abstracts
Cytomegalovirus infection is one of most frequent infectious complications after renal transplantation, and can be classified as primo-infection, when the transmission occurs through the graft, or reactivation, when the recipient is cytomegalovirus seropositive. After transplantation, cytomegalovirus can appear as an infection, when the patient presents with evidence of viral replication without symptoms or disease, which has two clinical spectra: typical viral syndrome or invasive disease, which is a less common form. Their effects can be classified as direct, while the disease is developed, or indirect, with an increase of acute rejection and chronic allograft dysfunction risks. Diagnosis must be made based on viremia by one of the standardized methods: antigenemia or PCR, which is more sensitive. The risk factors related to infection after transplantation are the serologic matching (positive donor and negative recipient) and anti-lymphocyte antibody drugs. One of the strategies to reduce risk of disease should be chosen for patients at high risk: preemptive treatment or universal prophylaxis. Recent clinical research has described ganciclovir resistance as an emergent problem in management of cytomegalovirus infection. Two types of mutation that cause resistance were described: UL97 (most frequent) and UL54. Today, sophisticated methods of immunologic monitoring to detect specific T-cell clones against cytomegalovirus are used in clinical practice to improve the management of high-risk patients after renal transplantation.
Cytomegalovirus; Kidney transplantation/complications; Kidney transplantation/physiopathology; Kidney transplantation/trends
A infecção pelo citomegalovírus é uma das principais complicações após o transplante de rim, podendo ser classificada em primoinfecção, quando a transmissão ocorre por meio do enxerto, ou em reativação, quando o receptor é soropositivo. Do ponto de vista clínico, pode se apresentar como infecção, na ausência de sintomas, ou como doença, com dois diferentes espectros: a síndrome viral típica ou, menos comumente, a doença invasiva. Os efeitos podem ser diretos, que é o desenvolvimento da doença, ou indiretos, como aumento no risco de rejeição aguda e de disfunção crônica do enxerto. O diagnóstico deve ser feito por pesquisa de viremia por meio de um dos dois métodos padronizados: antigenemia ou PCR − sendo essa última a mais sensível. Os fatores de risco relacionados com a infecção após o transplante são o match sorológico (doador positivo e receptor negativo) e o uso de anticorpos antilinfócitos. Uma das estratégias de redução de risco de doença deve ser escolhida após o transplante nos pacientes de alto risco: tratamento preemptivo ou profilaxia. Recentemente, linhas de pesquisa clínica têm apontado a resistência ao ganciclovir como um problema emergente no manejo da infecção pelo citomegalovírus. Duas formas de mutação que causam resistência são descritas: UL97, que é a mais frequente, e a UL54. Atualmente, sofisticados métodos de monitorização imunológica, como a detecção de clones específicos de células T contra o citomegalovírus podem ser utilizados na prática clínica para o melhor manejo após o transplante renal dos pacientes de alto risco.
Citomegalovírus; Transplante de rim/complicações; Transplante de rim/fisiopatologia; Transplante de rim/tendências
INTRODUCTION
Cytomegalovirus (CMV) is a human virus from the Herpesviridae family, a β-Herpesvirus
just as HHV-6 and HHV-7.(11 Pass FR. Epidemiology and transmission of cytomegalovirus. J Infect
Dis. 1985; 152(2):243-8. Review.) It is the largest known human herpesvirus, with
150 to 200nm in diameter, and is formed by a capsid of 162 proteins, an envelope
that contains lipoproteins and at least 33 structural proteins, of which
β-glycoprotein is the most important, and the core, with a double strand of DNA (64
nm).(11 Pass FR. Epidemiology and transmission of cytomegalovirus. J Infect
Dis. 1985; 152(2):243-8. Review.
2 Brennan DC. Cytomegalovirus in renal transplantation. J Am Soc
Nephrol. 2001;12(4):848-55. Review.-33 Humar A, Snydeman D; AST Infectiuos Diseases Community of Pratice.
Cytomegalovirus in solid organ transplant recipients. Am J Transplant. 2009;9
Suppl 4:S78-86.) In general, the first infection occurs in
childhood, and seroprevalence is 70 to 90% of the adult population.(44 Kasiske BL, Zeier MG, Chapman JR, Craig JC, Ekberg H, Garvey CA,
Green MD, Jha V, Josephson MA, Kiberd BA, Kreis HA, McDonald RA, Newmann JM,
Obrador GT, Vincenti FG, Cheung M, Earley A, Raman G, Abariga S, Wagner M, Balk
EM; Kidney Disease: Improving Global Outcomes. Clinical practice guideline for
the care of kidney transplant recipients: a summary. Kidney International.
2010;77(4):299-311.,55 Kuo HT, Ye X, Sampaio MS, Reddy P, Bunnapradist S. Cytomegalovirus
serostatus pairing and deceased donor kidney transplant outcomes in adult
recipients with antiviral prophylaxis. Transplantation.
2010;90(10):1091-8.) After the first infection, the presence
of the virus may be identified in subpopulations of CD34+ myeloid progenitors as
well as in CD14+ monocytes, dendritic cells, and megakaryocytes.(66 Paya CV. Prevention of cytomegalovirus disease in recipients of
solid-organ transplants. Clin Infect Dis. 2001;32(4):596-603.
Review.,77 Kotton CN, Fishman JA. Viral infection in the renal transplant
recipients. J Am Soc Nephrol. 2005;16(6):1758-74. Review.) In situations of immunosuppression,
such as AIDS (acquired immunodeficiency syndrome) and in solid organ transplants,
CMV reactivation may occur, causing a varied spectrum of clinical
manifestations.(66 Paya CV. Prevention of cytomegalovirus disease in recipients of
solid-organ transplants. Clin Infect Dis. 2001;32(4):596-603.
Review.) CMV infection is the primary infectious
complication in kidney transplantation, and it is one reason for high morbidity and
mortality rates.(22 Brennan DC. Cytomegalovirus in renal transplantation. J Am Soc
Nephrol. 2001;12(4):848-55. Review.)
OBJECTIVE
To present a review of the main clinical aspects of cytomegalovirus infection in renal transplants with a focus on clinical approach and its future perspectives.
METHODS
The present article was a critical and narrative review study based on relevant articles published about CMV infection in renal transplants. For review of the theme, the most relevant publications were selected based on PubMed, using as source for research descriptors such as “cytomegalovirus infection” and “kidney transplantation”. Previously published review articles were selected as well as studies designed to assess the following subthemes: clinical aspects, comparative studies of diagnostic methods that evaluated antigenemia or polymerase chain reaction (PCR), resistance to ganciclovir, and immunological monitoring. Additionally, data were presented from a longitudinal prospective cohort study that assessed the prevalence of CMV infection and the risk factors for its occurrence in 209 patients submitted to kidney transplants from cadaver donors at the Kidney Transplant Unit of Hospital Israelita Albert Einstein between 2002 and 2012.
Clinical aspects
In transplants, infection may occur as a primo-infection or as reactivation after
a long latency period. In all the candidates for kidney transplants, as well as
in all the donors, the serological status should be established by means of
identifying IgG class antibodies.(33 Humar A, Snydeman D; AST Infectiuos Diseases Community of Pratice.
Cytomegalovirus in solid organ transplant recipients. Am J Transplant. 2009;9
Suppl 4:S78-86.) A study that evaluated more than 20
thousand transplanted patients found the following distribution of serological
matchings as to the IgG status (D=donor and R=recipient): D+/R+=47.7%,
D-/R+=24.1%, D+/R-=18.2%, and D-/R-=10.3%.(55 Kuo HT, Ye X, Sampaio MS, Reddy P, Bunnapradist S. Cytomegalovirus
serostatus pairing and deceased donor kidney transplant outcomes in adult
recipients with antiviral prophylaxis. Transplantation.
2010;90(10):1091-8.) The serological status is a
long-term prognostic marker regardless of the development of the disease. When
D+/R- are compared with D-/R-, there is a 28% increase in risk of graft loss,
36% in the risk of death due to all causes, and eight-fold the risk of dying by
a viral infection. Serological typing, therefore, is indicated for all donors
and recipients.(44 Kasiske BL, Zeier MG, Chapman JR, Craig JC, Ekberg H, Garvey CA,
Green MD, Jha V, Josephson MA, Kiberd BA, Kreis HA, McDonald RA, Newmann JM,
Obrador GT, Vincenti FG, Cheung M, Earley A, Raman G, Abariga S, Wagner M, Balk
EM; Kidney Disease: Improving Global Outcomes. Clinical practice guideline for
the care of kidney transplant recipients: a summary. Kidney International.
2010;77(4):299-311.
5 Kuo HT, Ye X, Sampaio MS, Reddy P, Bunnapradist S. Cytomegalovirus
serostatus pairing and deceased donor kidney transplant outcomes in adult
recipients with antiviral prophylaxis. Transplantation.
2010;90(10):1091-8.-66 Paya CV. Prevention of cytomegalovirus disease in recipients of
solid-organ transplants. Clin Infect Dis. 2001;32(4):596-603.
Review.)
Primo-infection occurs in D+/R- recipients, in whom the viral infection is
transmitted by the transplanted organ.(33 Humar A, Snydeman D; AST Infectiuos Diseases Community of Pratice.
Cytomegalovirus in solid organ transplant recipients. Am J Transplant. 2009;9
Suppl 4:S78-86.
4 Kasiske BL, Zeier MG, Chapman JR, Craig JC, Ekberg H, Garvey CA,
Green MD, Jha V, Josephson MA, Kiberd BA, Kreis HA, McDonald RA, Newmann JM,
Obrador GT, Vincenti FG, Cheung M, Earley A, Raman G, Abariga S, Wagner M, Balk
EM; Kidney Disease: Improving Global Outcomes. Clinical practice guideline for
the care of kidney transplant recipients: a summary. Kidney International.
2010;77(4):299-311.
5 Kuo HT, Ye X, Sampaio MS, Reddy P, Bunnapradist S. Cytomegalovirus
serostatus pairing and deceased donor kidney transplant outcomes in adult
recipients with antiviral prophylaxis. Transplantation.
2010;90(10):1091-8.
6 Paya CV. Prevention of cytomegalovirus disease in recipients of
solid-organ transplants. Clin Infect Dis. 2001;32(4):596-603.
Review.-77 Kotton CN, Fishman JA. Viral infection in the renal transplant
recipients. J Am Soc Nephrol. 2005;16(6):1758-74. Review.) In recipients that carry the virus
there may be viral reactivation, and the primary risk factors identified are the
use of anti-lymphocyte antibodies (ALA), the type of immunosuppression protocol
used (type of drug, dose and duration), the treatment of acute rejection, and a
few factors related to the recipient, such as age, co-morbidities, and the
development of neutropenia.(88 Ozaki KS, Pestana JO, Granato CF, Pacheco-Silva A, Camargo LF.
Sequential cytomegalovirus antigenemia monitoring in kidney transplant patients
treated with antilymphocyte antibodies. Transplant Infec Dis.
2004;6(2):63-8.,99 Asberg A, Jardine AG, Bignamini AA, Rollag H, Pescovitz MD,
Gahlemann CC, Humar A, Hartmann A; VICTOR Study Group. Effects of the Intensity
of Immunosuppressive Therapy on Outcome of Treatment for CMV Disease in Organ
Transplant Recipients. Am J Transplant. 2010;10(8):1881-8.) Reactivation is related to reduction of
cellular immune activity, especially of CD8+ cells, as result of the
immunosuppressed state, and also due to activity of cytokines that induce the
virus to move from the state of latency, especially tumor necrosis factor alpha
(TNF-α) and interleukin-1β (IL-1β).(77 Kotton CN, Fishman JA. Viral infection in the renal transplant
recipients. J Am Soc Nephrol. 2005;16(6):1758-74. Review.
8 Ozaki KS, Pestana JO, Granato CF, Pacheco-Silva A, Camargo LF.
Sequential cytomegalovirus antigenemia monitoring in kidney transplant patients
treated with antilymphocyte antibodies. Transplant Infec Dis.
2004;6(2):63-8.
9 Asberg A, Jardine AG, Bignamini AA, Rollag H, Pescovitz MD,
Gahlemann CC, Humar A, Hartmann A; VICTOR Study Group. Effects of the Intensity
of Immunosuppressive Therapy on Outcome of Treatment for CMV Disease in Organ
Transplant Recipients. Am J Transplant. 2010;10(8):1881-8.
10 Roayaie S, Sheiner PA, Emre S, Guy S, Schwartz ME, Boros P, et al.
Cytokine profiles in early rejection following OKT3 treatment in liver
transplant patients. Mediators Inflamm. 2000;9(3-4):141-6.-1111 Sadegal S, Nordal KP, Hartmann A, Sund S, Scott H, Degré M, et al.
The impact of cytomegalovirus infection and disease on rejection episodes in
renal allograft recipients. Am J Transplant. 2002;2(9):850-6.) The use of ALA, besides causing
intense and prolonged lymphopenia, is related to the release of cytokines,
especially TNF-α.(33 Humar A, Snydeman D; AST Infectiuos Diseases Community of Pratice.
Cytomegalovirus in solid organ transplant recipients. Am J Transplant. 2009;9
Suppl 4:S78-86.
4 Kasiske BL, Zeier MG, Chapman JR, Craig JC, Ekberg H, Garvey CA,
Green MD, Jha V, Josephson MA, Kiberd BA, Kreis HA, McDonald RA, Newmann JM,
Obrador GT, Vincenti FG, Cheung M, Earley A, Raman G, Abariga S, Wagner M, Balk
EM; Kidney Disease: Improving Global Outcomes. Clinical practice guideline for
the care of kidney transplant recipients: a summary. Kidney International.
2010;77(4):299-311.
5 Kuo HT, Ye X, Sampaio MS, Reddy P, Bunnapradist S. Cytomegalovirus
serostatus pairing and deceased donor kidney transplant outcomes in adult
recipients with antiviral prophylaxis. Transplantation.
2010;90(10):1091-8.
6 Paya CV. Prevention of cytomegalovirus disease in recipients of
solid-organ transplants. Clin Infect Dis. 2001;32(4):596-603.
Review.-77 Kotton CN, Fishman JA. Viral infection in the renal transplant
recipients. J Am Soc Nephrol. 2005;16(6):1758-74. Review.) Acute rejection, in addition to requiring
intensification of immunosuppression, causes an increased expression of IL-1β,
which is a cytokine that stimulates viral replication (Figure 1).(77 Kotton CN, Fishman JA. Viral infection in the renal transplant
recipients. J Am Soc Nephrol. 2005;16(6):1758-74. Review.)
After the occurrence of viral activation (whether in primo-infection or reactivation), an infection by CMV may be classified in two ways, according to its clinical presentation as infection or disease.(1212 Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Snydman DR, Allen U, Humar A; Transplantation Society International CMV Consensus Group. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation. 2010;89(7):779-95.,1313 Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Danziger-Isakov L, Humar A; Transplantation Society International CMV Consensus Group. Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation. 2013;96(4):333-60.) In CMV infection, there is evidence of viral replication in the absence of symptoms. This presentation is different from latency, because in latency there is no evidence of active viral replication. On the other hand, CMV disease is characterized by the clinical syndrome in which there are symptoms, such as fever, asthenia, myalgia, leukopenia, thrombocytopenia, or hepatic enzyme alterations, or by the invasive disease, in which there is evidence of viral inclusion in cells of organs or tissues, such as in the gastrointestinal tract, liver, in the renal graft, lungs, bone marrow and retina. The effects of CMV infection can be classified as direct or indirect (Figure 1). The direct effects are infection and disease, as mentioned above. The indirect effects observed are increased risk of secondary infections, such as pneumocystosis and other herpesviruses, and increased risk of acute rejection and of chronic graft dysfunction.(77 Kotton CN, Fishman JA. Viral infection in the renal transplant recipients. J Am Soc Nephrol. 2005;16(6):1758-74. Review.) CMV infection can trigger a general immunostimulatory response, with concomitant antigenic stimulation. Hence, CMV has always been considered a potential risk factor for acute rejection of grafts, especially in lung transplants. In a study with 477 patients with transplanted kidneys, with a 38% prevalence of acute rejection confirmed by biopsy, 64% of infection by CMV, and 24% of disease, the authors observed that infection and the disease by CMV increased the risk of acute rejection by 1.6- and 2.5-fold, respectively.(1111 Sadegal S, Nordal KP, Hartmann A, Sund S, Scott H, Degré M, et al. The impact of cytomegalovirus infection and disease on rejection episodes in renal allograft recipients. Am J Transplant. 2002;2(9):850-6.)
There is evidence that CMV may be related to chronic vascular alterations and can
influence the development of bronchiolitis obliteratens in lung transplants,
accelerated coronary artery disease in heart transplants, and chronic vascular
disease in kidney transplants.(1414 Kroshus TJ, Kshettry VR, Savik K, John R, Hertz MI, Bolman RM 3rd.
Risk factors for the development of bronchiolitis obliterans syndrome after lung
transplantation. J Thorac Cardiovasc Surg. 1997;114(2):195-202.
15 Helanterä I, Koskinen P, Tõrnroth T, Loginov R, Gronhagen-Riska C,
Lautenschlager I. The impact of cytomegalovirus infections and acute rejection
episodes on the development of vascular changes in 6-month protocol biopsy
specimens of cadaveric kidney allograft recipients. Transplantation.
2003;75(11):1858-64.-1616 Potena L, Valantine HA. Cytomegalovirus-associated allograft
rejection in heart transplant recipients. CurrOpin Infect Dis.
2007;20(4):425-31. Review.) The impact of the indirect effects of
CMV in several renal compartments is the object of speculation. Reischiget et
al. demonstrated that viremia by CMV measured by PCR was related to the
increased risk of interstitial fibrosis and tubular atrophy (IF/TA) in protocol
biopsies, 3 months after the kidney transplant.(1717 Reischig T, Jindra P, Hes O, Bouda M, Kormunda S, Treska V. Effect
of cytomegalovirus viremia on subclinical rejection or interstitial fibrosis and
tubular atrophy in protocol biopsy at 3 months in renal allograft recipients
managed by preemptive therapy or antiviral prophylaxis. Transplantation.
2009;87(3):436-44.) In this study, however, patients
who had chronic alterations were those who had more acute rejection, but it was
not possible to associate CMV infection with an inducing factor of fibrosis.
In the kidney transplant program of Hospital Israelita Albert Einstein, a total of 209 kidney transplanted patients with deceased donors were evaluated in a consecutive manner for one decade. They were all induced with thymoglobulin (an ALA), and therefore with risk of developing the infection. Only 11.5% of the recipients had IgG negative for CMV before transplant. The prevalence of CMV infection among these patients was 63.4%, and when the characteristics of the patients who had infection were compared to those who did not have infection (Table 1), we only observed a greater time of cold ischemia among those who had the infection (22.9±5.7 versus 21.2±5.9 hours; p=0.03). The time to diagnosis of the infection was 45.0±15.6 days, and of these, 11 patients presented with it 3 months after transplant, with a prevalence of late infection of 7.3%. As to the clinical picture, 43.7% had infection and 52.3%, disease; of these, 9.3% had invasive disease (Figure 2). The diagnosis was performed with a mean of 80.0±136.0 infected cells in pp65 antigenemia. One single episode of infection occurred in 55.8% of patients, at least one relapse in 33.3%, and more than one relapse in 10.9% (Figure 2).
Clinical presentation and need for retreatment of cytomegalovirus infection in the Kidney Transplant Program of the Hospital Israelita Albert Einstein
DIAGNOSIS: ANTIGENEMIA AND PCR
Histopathology, serology (IgM) and cell cultures were frequently used in the past for
diagnosis of CMV, but should no longer be utilized due to their low sensitivity and
technical difficulties.(1212 Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Snydman DR, Allen
U, Humar A; Transplantation Society International CMV Consensus Group.
International consensus guidelines on the management of cytomegalovirus in solid
organ transplantation. Transplantation. 2010;89(7):779-95.,1313 Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Danziger-Isakov
L, Humar A; Transplantation Society International CMV Consensus Group. Updated
international consensus guidelines on the management of cytomegalovirus in
solid-organ transplantation. Transplantation.
2013;96(4):333-60.) Histopathology requires tissue biopsies, and
despite being definitive when the viral inclusions are found, it is not very
sensitive and only allows the diagnosis of invasive disease.(33 Humar A, Snydeman D; AST Infectiuos Diseases Community of Pratice.
Cytomegalovirus in solid organ transplant recipients. Am J Transplant. 2009;9
Suppl 4:S78-86.) It may be useful in
clinically suspect cases when viremia is negative. The detection of IgM should not
be used for diagnosis of active infection in transplants because the titles of IgM
are not detected early, because they are related to the late initiation of
treatment. Cell cultures present good sensitivity, indicating CMV activity when
positive, but requiring 1 to 3 weeks for confirmation of a negative
result.(33 Humar A, Snydeman D; AST Infectiuos Diseases Community of Pratice.
Cytomegalovirus in solid organ transplant recipients. Am J Transplant. 2009;9
Suppl 4:S78-86.
4 Kasiske BL, Zeier MG, Chapman JR, Craig JC, Ekberg H, Garvey CA,
Green MD, Jha V, Josephson MA, Kiberd BA, Kreis HA, McDonald RA, Newmann JM,
Obrador GT, Vincenti FG, Cheung M, Earley A, Raman G, Abariga S, Wagner M, Balk
EM; Kidney Disease: Improving Global Outcomes. Clinical practice guideline for
the care of kidney transplant recipients: a summary. Kidney International.
2010;77(4):299-311.
5 Kuo HT, Ye X, Sampaio MS, Reddy P, Bunnapradist S. Cytomegalovirus
serostatus pairing and deceased donor kidney transplant outcomes in adult
recipients with antiviral prophylaxis. Transplantation.
2010;90(10):1091-8.
6 Paya CV. Prevention of cytomegalovirus disease in recipients of
solid-organ transplants. Clin Infect Dis. 2001;32(4):596-603.
Review.-77 Kotton CN, Fishman JA. Viral infection in the renal transplant
recipients. J Am Soc Nephrol. 2005;16(6):1758-74. Review.)
The most sensitive and recommended methods for diagnosis are based on viral load, and
can be performed by pp65 antigenemia or PCR.(1818 Rhee JY, Peck KR, Lee NY, Song JH. Clinical usefulness of plasma
quantitative polymerase chain reaction assay: diagnosis of cytomegalovirus
infection in kidney transplant recipients. Transplant Proc.
2011;43(7):2624-9.,1919 Camargo LF, Uip DE, Simpson AA, Caballero O, Stolf NA, Vilas-Boas
LS, et al. Comparison between antigenemia and a quantitative-competitive
polymerase chain reaction for the diagnosis of cytomegalovirus infection after
heart transplantation. Transplantation. 2001;71(3):412-7.) A positive viral load by one of these
methods is an independent indicator of risk for CMV disease. Viremia is an
indispensable tool for initiating and following up treatment. During viral
replication, three types of antigens are produced: immediate, early, and
late.(2020 Gandhi MK, Khanna R. Human cytomegalovirus: clinical aspects, immune
regulation, and emerging treatments. Lancet Infect Dis. 2004;4(12):725-38.
Review.) Immediate antigens appear in the nucleus of
the infected cells 1 to 3 hours after infection, and persist during the latent
infection. The early antigens appear in the cytoplasm 3 hours after infection, even
before the beginning of DNA synthesis. The late antigens are structural proteins and
only appear after the synthesis of DNA, and therefore are associated with active
infection. One of the late agents is pp65 antigen and can be identified within the
cytoplasm of leukocytes by immunofluorescence, a technique called “pp65
antigenemia”.(1919 Camargo LF, Uip DE, Simpson AA, Caballero O, Stolf NA, Vilas-Boas
LS, et al. Comparison between antigenemia and a quantitative-competitive
polymerase chain reaction for the diagnosis of cytomegalovirus infection after
heart transplantation. Transplantation. 2001;71(3):412-7.
20 Gandhi MK, Khanna R. Human cytomegalovirus: clinical aspects, immune
regulation, and emerging treatments. Lancet Infect Dis. 2004;4(12):725-38.
Review.
21 Gerna G, Baldanti F, Lilleri D, Parea M, Torsellini M, Castiglioni
B, et al. Human cytomegalovirus pp67 mRNAemia versus pp65 antigenemia for
guiding preemptive therapy in heart and lung transplant recipients: a
prospective, randomized, controlled, open-label trial. Transplantation.
2003;75(7):1012-9.
22 Schröeder R, Michelon T, Fagundes I, Bortolotto A, Lammerhirt E,
Oliveira J, et al. Antigenemia for cytomegalovirus in renal transplantation:
choosing a cut off for the diagnosis criteria in cytomegalovirus disease.
Transplant Proc. 2005;37(6):2781-3.-2323 Baldanti F, Lilleri D, Gerna G. Monitoring human cytomegalovirus
infection in transplant recipients. J Clin Virol. 2008;41(3):237-41.
Review.) This method has the advantage of being quick,
with results given on the same day of collection, but it requires a trained team and
its sensitivity is reduced if the blood is processed after 6 hours.
The gold standard for diagnosis of CMV is the quantitative nucleic acid testing
(QNAT). QNAT-CMV has been performed preferentially by real time PCR (RT-PCR), using
plasma or total blood. The qualitative standard indicates CMV in activity, but has
no direct relation with the presence of the disease, which requires quantification.
Therefore, the viral load detected by PCR has high predictive power for the disease
and should be preferred. Contrary to antigenemia, sensitivity is not altered by
blood storage, and can be transported for its use in distant centers. Its
disadvantages are the lack of standardization among the centers, with discordance as
to the results under inter-center analysis and need for greater time to perform,
when compared to antigenemia.(2424 Lao WC, Lee D, Burroughs AK, Lanzani G, Rolles K, Emery VC, et al.
Use of polymerase chain reaction to provide prognostic information of human
cytomegalovirus disease after liver transplantation. J Med Virol.
1997;51(3):152-8.
25 Caliendo AM, St George K, Allega J, Bullotta AC, Gilbane L, Rinaldo
CR, et al. Distinguishing cytomegalovirus (CMV) infection and disease with CMV
nucleic acid assays. J Clin Microbiol. 2002;40(5):1581-6
26 Rollag H, Sagedal S, Kristiansen KI, Kvale D, Holter E, Degré M, et
al. Cytomegalovirus DNA concentration in plasma predicts development of
cytomegalovirus disease in kidney transplant recipients. Clin Microbiol Infect.
2002; 8(7):431-4.-2727 Razonable RR, van Cruijsen H, Brown RA, Wilson JA, Harmsen WS,
Wiesner RH, et al. Dynamics of cytomegalovirus replication during preemptive
therapy with oral ganciclovir. J Infect Dis.
2003;187(11):1801-8.)
RISK REDUCTION AND INFECTION TREATMENT STRATEGY
Two strategies of risk reduction for the CMV disease are currently available and should be adopted in high-risk patients: preemptive treatment and universal prophylaxis.(44 Kasiske BL, Zeier MG, Chapman JR, Craig JC, Ekberg H, Garvey CA, Green MD, Jha V, Josephson MA, Kiberd BA, Kreis HA, McDonald RA, Newmann JM, Obrador GT, Vincenti FG, Cheung M, Earley A, Raman G, Abariga S, Wagner M, Balk EM; Kidney Disease: Improving Global Outcomes. Clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney International. 2010;77(4):299-311.,66 Paya CV. Prevention of cytomegalovirus disease in recipients of solid-organ transplants. Clin Infect Dis. 2001;32(4):596-603. Review.,1212 Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Snydman DR, Allen U, Humar A; Transplantation Society International CMV Consensus Group. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation. 2010;89(7):779-95.,1313 Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Danziger-Isakov L, Humar A; Transplantation Society International CMV Consensus Group. Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation. 2013;96(4):333-60.) High-risk patients are considered those with a serological match D+/R- or those who received some kind of ALA treatment. The positive IgG recipients are considered of intermediate risk and may also benefit from one of the strategies. Universal prophylaxis consists in the administration of an antiviral for the period of 3 to 6 months. Current evidence demonstrates that the use of valaciclovir is not adequate for prophylaxis, and ganciclovir (orally) and valganciclovir are used. In addition to the prolonged exposure to the drug, which may increase the risk of resistance and side effects, universal prophylaxis is associated with the late onset disease, with an incidence of up to 18% after discontinuation of the medication. The preemptive treatment consists of intense monitoring of viremia, weekly between the 21st and the 90th postoperative days (and can be continued for more time depending on the progression of the patient and intensity of the immunesuppression), initiating treatment with intravenous ganciclovir or valganciclovir in patients with positive viremia. Besides lower cost and less exposure to the drug, the preemptive treatment is associated with a lower risk of late onset disease. One potential disadvantage of this strategy is that it allows exposure to viremia more frequently than prophylaxis, which would not avoid the indirect effects of the virus; however, comparative studies showed that viremia may also occur during prophylaxis, but with less prevalence.
The treatment of CMV infection should be done with intravenous ganciclovir for 14 to 28 days. Asymptomatic patients or those with disease, but with no severity criteria, can be treated with valganciclovir. If the investigation of viremia is done with antigenemia, we suggest maintaining the treatment for 1 week after obtaining negative result, since that is the period in which PCR persists as positive. Patients with invasive disease should be treated for 21 to 28 days. In children, or in cases of the first infection, as well as in patients with low doses of immunoglobulins, one can use polyclonal immunoglobulin or the one specific against CMV, as adjuvant treatments.
RESISTANCE INVESTIGATION
Since both universal prophylaxis and preemptive treatment have exposed the patients to frequent and prolonged use of ganciclovir, there is a risk of CMV developing resistance to the drug (CMV-R). Besides the prolonged use of the antiviral, the serological D+/R- match and the late viral eradication after initiating treatment are mentioned as the primary risk factors for developing resistance.(2828 Limaye AP, Corey L, Koelle DM, Davis CL, Boeckh M. Emergence of ganciclovir-resistent cytomegalovirus disease among recipients of solid-organ transplant. Lancet. 2000;356(9230):645-50. Review.) Resistance is caused by mutation in two genes, UL97 and UL54, and the former is the most important and the most frequent. The incidence of CMV-R reaches 20% in AIDS patients with retinitis after 9 months of treatment, and can be related to time of exposure to the drug.(2929 Jabs DA, Martin BK, Forman MS, Dunn JP, Davis JL, Weinberg DV, Biron KK, Baldanti F; Cytomegalovirus Retinitis and Viral Resistance Study Group. Mutations conferring ganciclovir resistance in a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis. J Infect Dis. 2001;183(2):333-7.) In a study that evaluated 1,244 kidney transplant recipients, Myhre et al. identified resistance to ganciclovir in 27 patients (2.2%); in that, 26 had the serological match D+/R-.(3030 Myhre HA, Dorenberg DH, Kristiansen KI, Rollag H, Leivestad T, Asberg A, et al. Incidence and outcomes of ganciclovir-resistant cytomegalovirus infections in 1244 kidney transplant recipients. Transplantation. 2011;92(2):217-23.) Treatment of CMV-R may be done with high doses of intravenous ganciclovir (up to 10mg/kg/dose), or more appropriately, with foscarnet or cidofovir. The limitation for use of these last two drugs is their potential renal toxicity. Câmara et al. assessed a series of nine patients with kidney or pancreas-kidney transplants with CMV-R, in which the calcineurin inhibitor or mycophenolate was substituted by sirolimus, an inhibitor of mammalian target of rapamycin (mTOR). Treatment with ganciclovir was maintained and among these patients only one required the use of foscarnet, demonstrating that mTOR inhibitors can have an adjunctive function in treating infection by CMV-R.(3131 Câmara NO, Ozaki KS, Nogueira E, Pereira MG, Granato C, Melaragno C, et tal. The use of sirolimus in ganciclovir-resistant cytomegalovirus infections in renal transplant recipients. Clinical Transplantation. 2007;21(5):675-80.)
PERSPECTIVE: IMMUNOLOGIC MONITORING
After transplant, a few immune markers may be used to define patients with greater sensitivity for infection, and lately, the determination of these markers by means of sophisticated laboratorial tests has become a frequently used tool in research and should reach clinical practice within the next few years.(1212 Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Snydman DR, Allen U, Humar A; Transplantation Society International CMV Consensus Group. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation. 2010;89(7):779-95.,1313 Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Danziger-Isakov L, Humar A; Transplantation Society International CMV Consensus Group. Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation. 2013;96(4):333-60.) There are lines of research with promising results both in innate immunity markers and in cell adaptive immunity.
Natural killer (NK) cells, components of the innate immune system, play an important role in virus clearance in experimental models of CMV infection. Mice with NK ablation are susceptible to lethal infection. Adult mice resistant to CMV infection become sensitive when they are depleted of NK cells.(3232 Polic B, Hengel H, Krmpotic A, Trgovcich J, Pavić I, Luccaronin P, et al. Hierarchical and redundant lymphocyte subset control precludes cytomegalovirus replication during latent infection. J Exp Med. 1998;188(6):1047-54.) Patients with deficiency in NK cells present with recurring herpetic infection, including pneumonitis due to CMV. In a study with 43 patients submitted to bone marrow transplants that presented with CMV reactivation, the capacity to recover from the infection was associated with the activity of the NK cells.(3333 Quinnan GV, Kirmani N, Rook AH, Manischewitz JF, Jackson L, Moreschi G, et al. Cytotoxic T cells in cytomegalovirus infection: HLA-restricted T-lymphocyte and non-T-lymphocyte cytotoxic responses correlate with recovery from cytomegalovirus infection in bone-marrow-transplant recipients. N Eng J Med. 1982;307(1):7-13.)
Another component of the innate immune system that can be related with CMV infection
is the third pathway of the complement. This via, called “mannose-binding lecithin”
(MBL), is activated by MBL itself, which has characteristics similar to the C1q
molecule, with four subunits denominated MASP (MBL – associated serine protease).
Through MASP 1 and 2, the C2 and C4 fractions of the complement are cleaved to C3
convertase, thus activating the common pathway.(3434 Janeway CA, Travers P, Walport M, Shlomchik MJ. Munobiologia: o
sistema imune na saúde e na doença. 6a ed. São Paulo: Artmed; 2006. Imunidade
adaptativa contra infecção. p. 357-66) This pathway seems to play an
important role in the innate response of immunosuppressed children and individuals.
Circulating MBL is organized into oligomeric structures, facilitating multivalent
bonding with microbial components. MBL2 polymorphism can produce a defective MBL in
the polymerization process, and is associated with low serum levels and reduction of
its activity.(3535 Madsen HO, Garred P, Kurtzhals JA, Lamm LU, Ryder LP, Thiel S, et
al. A new frequent allele is the missing link in the structural polymorphism of
the human mannan-binding protein.
Immunogenetics.1994;40(1):37-44.) MBL deficiency is related to recurring
meningitis by HSV-2, symptomatic genital herpes, susceptibility to HIV infection, as
well as the earlier development of AIDS in infected patients, to meningococcal
disease and to bacterial infections in liver transplant.(3636 Hibberd ML, Sumiya M, Summerfield JA, Booy R, Levin M. Association
of variants of the gene for mannose-binding lectin with susceptibility to
meningococcal disease. Meningococcal Research Group. Lancet.
1999;353(9158):1049-53.
37 Peterslund NA, Koch C, Jensenius JC, Thiel S. Association between
deficiency of mannose-binding lectin and severe infections after chemotherapy.
Lancet. 2001;358(9282):637-8.-3838 Bouwman LH, Roos A, Terpstra OT, de Knijff P, van Hoek B, Verspaget
HW, et al. Mannose binding lectin gene polymorphisms confer a major risk for
severe infections after liver transplantation. Gastroenterology.
2005;129(2):408-14.) In a study performed in patients with
transplanted kidneys, Manuel et al. identified that the serum levels of MBL were
significantly lower in patients who had CMV infection (2.445mg/mL
versus 97mg/mL; p=0.004; cutoff point at 500mg/mL). In this
same study, in which all the individuals included were D+/R-, the deficiency was
diagnosed in 71% of cases of invasive disease, while there was no patient with the
deficiency among those who did not present with the infection after transplant,
despite the high-risk serological match.(3939 Manuel O, Pascual M, Trendelenburg M, Meylan PR. Association between
mannose-binding lectin deficiency and cytomegalovirus infection after kidney
transplantation. Transplantation. 2007;83(3):359-62.)
Adaptive response activity can also be measured.(4040 Radha R, Jordan S, Puliyanda D, Bunnapradist S, Petrosyan A, Amet N, et al. Cellular immune response to cytomegalovirus in renal transplant recipients. Am J Transplant. 2005;5(1):110-7.) In an elegant study, Radha et al., described that after the primo-infection, CMV leaves its digital impression in pools of CD8+ and CD4+ T-cells. The response of these cells in the presence of certain antigens of the CMV can be measured by a few methods, such as major histocompatibility complex (MHC) tetramers, Enzyme-Linked ImmunoSpot (ELISPOT), and flow cytometry of cytokines, the latter of which is the most frequently used. When CD4+ and CD8+ cells of patients who have already had the infection are treated with lysates of antigens such as pp65 and EI, the pool of specific cells against CMV can be identified through the quantity of interferon-gamma (IFN-δ) produced. In a study that evaluated 108 patients transplanted with solid organs, with prevalence of infection of 16.7%, Humar et al. described measuring activity of the immune system (cell-mediated immunity – CMI) specific against CMV falls significantly soon after the transplant and then progressively increases in the subsequent months.(33 Humar A, Snydeman D; AST Infectiuos Diseases Community of Pratice. Cytomegalovirus in solid organ transplant recipients. Am J Transplant. 2009;9 Suppl 4:S78-86.) During pre-transplant, approximately 50% of the patients had positive CMI, which occurred in only 15.7% and 27.6% in the first and third months after the transplant, respectively. The capacity for recovery from CMI was related to the risk of developing infection. The frequency of CMV disease was 20% among the patients with negative CMI, whereas in those with positive CMI, it was less than 5% (p=0.04).
CONCLUSIONS
Cytomegalovirus infection is one of the main infectious morbidities after renal transplant, leading to direct effects, such as disease, characterized by the viral syndrome or by the invasive disease, and to indirect effects, such as increased risk of acute rejection and chronic graft dysfunction. The diagnosis should be made proactively, using sensitive forms of viremia identification: antigenemia or polymerase chain reaction. One emergent problem in managing patients with cytomegalovirus is infection resistant to ganciclovir, which may be treated with other antivirals or with mTOR-inhibitors. Immunologic monitoring plays a promising role in identifying patients with the potential of progressing in an unfavorable manner and it is a tool that should be added to clinical practice on a large scale.
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27Razonable RR, van Cruijsen H, Brown RA, Wilson JA, Harmsen WS, Wiesner RH, et al. Dynamics of cytomegalovirus replication during preemptive therapy with oral ganciclovir. J Infect Dis. 2003;187(11):1801-8.
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28Limaye AP, Corey L, Koelle DM, Davis CL, Boeckh M. Emergence of ganciclovir-resistent cytomegalovirus disease among recipients of solid-organ transplant. Lancet. 2000;356(9230):645-50. Review.
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29Jabs DA, Martin BK, Forman MS, Dunn JP, Davis JL, Weinberg DV, Biron KK, Baldanti F; Cytomegalovirus Retinitis and Viral Resistance Study Group. Mutations conferring ganciclovir resistance in a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis. J Infect Dis. 2001;183(2):333-7.
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30Myhre HA, Dorenberg DH, Kristiansen KI, Rollag H, Leivestad T, Asberg A, et al. Incidence and outcomes of ganciclovir-resistant cytomegalovirus infections in 1244 kidney transplant recipients. Transplantation. 2011;92(2):217-23.
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31Câmara NO, Ozaki KS, Nogueira E, Pereira MG, Granato C, Melaragno C, et tal. The use of sirolimus in ganciclovir-resistant cytomegalovirus infections in renal transplant recipients. Clinical Transplantation. 2007;21(5):675-80.
-
32Polic B, Hengel H, Krmpotic A, Trgovcich J, Pavić I, Luccaronin P, et al. Hierarchical and redundant lymphocyte subset control precludes cytomegalovirus replication during latent infection. J Exp Med. 1998;188(6):1047-54.
-
33Quinnan GV, Kirmani N, Rook AH, Manischewitz JF, Jackson L, Moreschi G, et al. Cytotoxic T cells in cytomegalovirus infection: HLA-restricted T-lymphocyte and non-T-lymphocyte cytotoxic responses correlate with recovery from cytomegalovirus infection in bone-marrow-transplant recipients. N Eng J Med. 1982;307(1):7-13.
-
34Janeway CA, Travers P, Walport M, Shlomchik MJ. Munobiologia: o sistema imune na saúde e na doença. 6a ed. São Paulo: Artmed; 2006. Imunidade adaptativa contra infecção. p. 357-66
-
35Madsen HO, Garred P, Kurtzhals JA, Lamm LU, Ryder LP, Thiel S, et al. A new frequent allele is the missing link in the structural polymorphism of the human mannan-binding protein. Immunogenetics.1994;40(1):37-44.
-
36Hibberd ML, Sumiya M, Summerfield JA, Booy R, Levin M. Association of variants of the gene for mannose-binding lectin with susceptibility to meningococcal disease. Meningococcal Research Group. Lancet. 1999;353(9158):1049-53.
-
37Peterslund NA, Koch C, Jensenius JC, Thiel S. Association between deficiency of mannose-binding lectin and severe infections after chemotherapy. Lancet. 2001;358(9282):637-8.
-
38Bouwman LH, Roos A, Terpstra OT, de Knijff P, van Hoek B, Verspaget HW, et al. Mannose binding lectin gene polymorphisms confer a major risk for severe infections after liver transplantation. Gastroenterology. 2005;129(2):408-14.
-
39Manuel O, Pascual M, Trendelenburg M, Meylan PR. Association between mannose-binding lectin deficiency and cytomegalovirus infection after kidney transplantation. Transplantation. 2007;83(3):359-62.
-
40Radha R, Jordan S, Puliyanda D, Bunnapradist S, Petrosyan A, Amet N, et al. Cellular immune response to cytomegalovirus in renal transplant recipients. Am J Transplant. 2005;5(1):110-7.
Publication Dates
-
Publication in this collection
Jan-Mar 2015
History
-
Received
5 May 2014 -
Accepted
26 Feb 2015