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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 1  |  Page : 19-24

Cytomegalovirus infection in solid malignancies


Department of Medical Oncology, Tata Memorial Hospital; Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India

Date of Submission07-Dec-2019
Date of Decision22-Dec-2019
Date of Acceptance07-Jan-2020
Date of Web Publication24-Feb-2020

Correspondence Address:
Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_112_19

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  Abstract 


Introduction: Cytomegalovirus (CMV) infection is very common, although its manifestation as disease occurs usually in the setting of immunosuppression. It is usually seen in hematological malignancies and in post-transplant recipient patients. Data about CMV reactivation in solid malignancies are limited.
Materials and Methods: This was a retrospective analysis of adult patients (from the past 10 years of clinical records) with various solid malignancies, who had CMV deoxyribonucleic acid (DNA) positivity and had varied clinical presentation.
Results: Of total 73 adult patients of solid malignancies who had been tested for CMV DNA (by real-time polymerase chain reaction [RT-PCR]) with a detection limit of 150 copies/ml), 30 patients had at least one instance of CMV DNA positivity. Of them, we were able to obtain detailed records of 17 patients, who had CMV DNA positivity with clinical manifestations. Fever was the most common symptom in 88% of patients. CMV DNA copy numbers in these patients ranged from 250 to 1,490,000 copies/ml (by RT-PCR). Twelve of the 17 patients (71%) had positive tests for other microbes (based on culture testing) besides the positive CMV test. Ten of 17 (59%) patients were treated with ganciclovir and 7 patients responded to treatment. Seven patients (3 treated with ganciclovir and 4 remained untreated) died during the hospital course. Ten patients recovered (7 treated with ganciclovir and 3 remained untreated, with only monitoring of CMV DNA levels) of their acute illness.
Conclusion: CMV infection and its manifestation in patients with solid malignancies is probably underdiagnosed. Given the high morbidity and mortality in these patients (with or without co-infections), it is very important to suspect and treat CMV reactivation.

Keywords: Cytomegalovirus, cytomegalovirus reactivation, CMV, solid malignancies


How to cite this article:
Agrawal AK, Rajendra A, Noronha V, Joshi A, Patil VM, Menon N, Talreja V, Prabhash K. Cytomegalovirus infection in solid malignancies. Cancer Res Stat Treat 2020;3:19-24

How to cite this URL:
Agrawal AK, Rajendra A, Noronha V, Joshi A, Patil VM, Menon N, Talreja V, Prabhash K. Cytomegalovirus infection in solid malignancies. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Apr 10];3:19-24. Available from: http://www.crstonline.com/text.asp?2020/3/1/19/279070




  Introduction Top


Cytomegalovirus (CMV) infection is very common, particularly in developing countries. CMV infection implies isolation of the virus or detection of viral proteins (antigens) or nucleic acid in any body fluid or tissue specimen regardless of symptoms or signs.[1] As per the official definition, isolation of CMV by culture is called CMV viremia, while detection of CMV antigen or CMV deoxyribonucleic acid (DNA) is labeled as CMV antigenemia and CMV DNAemia, respectively. However, CMV infection resulting in clinical manifestations with attributable signs and symptoms (termed as CMV disease) is rare in immunocompetent individuals and usually occurs in the setting of immunosuppression.[2] CMV is a beta-herpesvirus, which after infection remains latent inside the cells of the hematopoietic system. There are certain processes occurring at the molecular and cellular level, which lead to overall suppression of viral lytic gene expression. Experiments suggest that probably the expression of non-coding RNAs during this period helps to maintain latency by modulating the host cell responses. The mechanism of how and when it gets reactivated is not completely understood, however one potential trigger is the differentiation of hematopoietic cells into macrophages and dendritic cells.[3] Common conditions in which CMV reactivation occurs include patients with hematological malignancies, hematopoietic stem cell transplant recipients, solid organ transplant recipients, human immunodeficiency virus (HIV) infection, and other immunodeficiency conditions (like patients on immunomodulatory drugs).[4] In immunocompetent individuals too, sometimes the presence of certain diseases and inflammation can trigger CMV reactivation.[5] In terms of clinical manifestations, CMV disease can have varied presentations ranging from viral syndromes (i.e., CMV viremia associated with fever, malaise, and cytopenias) to tissue-invasive disease (manifestation depending on the site of involvement such as hepatitis, pneumonia, colitis, encephalitis, esophagitis, and retinitis).[1] This reactivation can lead to significant morbidity and mortality. Therefore, in the post-transplant setting, the CMV viral load is monitored and prophylaxis and preemptive treatment strategies are used to prevent overt disease/manifestations.

In terms of incidence, solid tumors are more common than hematological malignancies.[6] As opposed to hematological malignancies, systemic therapy for solid tumors does not lead to profound immunosuppression and the duration of neutropenia is generally short. Factors which play an important role in causing infection in these solid tumor patients include damage of the normal anatomical barriers (skin, mucosa), obstructive phenomena (seen in lung, hepatobiliary, gynecological, urinary tract, and colorectal malignancies), surgical procedures, chemotherapy, radiation therapy, poor nutrition, and use of medical devices (such as catheters, stents, shunts, and prosthesis).[7] These infections are usually caused by bacteria (now commonly occurring with resistant strains), occasionally fungal infections, parasites (like malaria), and rarely viral infections/reactivations (such as hepatitis B, hepatitis C, and rarely CMV).

CMV reactivation is less common in solid malignancies due to less severe immunosuppression.[8] Scanty data are available regarding its prevalence and clinical significance in patients with solid malignancies. Another important factor is that we routinely do not investigate for CMV reactivation in patients with solid malignancies; so, the exact prevalence and associated morbidity/mortality of CMV reactivation in patients with solid tumors are unknown. We performed a retrospective analysis to find the clinical impact of CMV reactivation in our patients with solid malignancies.


  Materials and Methods Top


This was a retrospective analysis conducted at Tata Memorial Hospital in Mumbai, a tertiary care cancer hospital in India. We reviewed the past 10 years' records (from year 2010 to 2019) and identified the list of adult patients (>15 years of age at the time of diagnosis of malignancy) with solid tumors, who had at least one episode of CMV DNA positivity. The method used to detect CMV in these patients was detection of CMV viral load through real time polymerase chain reaction (RT-PCR). We used a cut-off of >150 copies/ml as the threshold to label the test positive. Although in the strict sense, this should be termed as CMV DNAemia, it can indirectly be interpreted as CMV viremia. Of these patients, we only included those patients in our data analysis whose detailed records were available on our electronic medical record system. Information collected included demographics, details of underlying malignancy and ongoing therapy, and clinical presentation at the time when CMV viremia was documented. The clinical details collected included the presenting features, investigations, therapy, complications and outcome of CMV infections/reactivation. Data were then entered in an excel worksheet and analyzed with simple percentages. The study was conducted according to the principles of Good Clinical Practice and adhered to the Principles of Helsinki and Indian Council of Medical Research guidelines.


  Results Top


Patient characteristics

There were total 73 adult patients of solid malignancies who had been tested for CMV DNA. Amongst them, 30 patients had at least one instance of CMV DNA positivity (CMV DNA copy number >150 copies/ml). Out of them, complete records were available for 17 patients. The median age of these 17 patients was 44 years (range, 17–71 years). These patients had varied sites of tumor primary as well as histology, as mentioned in [Table 1]. The type of anticancer treatment at the time of CMV reactivation and intent of the treatment are also detailed in [Table 1]. The median duration of systemic anticancer treatment before the diagnosis of CMV reactivation was 1.5 months (range, 1–12 months). The median time from diagnosis of malignancy to documentation of CMV reactivation was 4 months (range, 1–21 months).
Table 1: Baseline demographic and disease-related details of the patients with solid tumor malignancies who developed cytomegalovirus reactivation (n=17)

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Two patients had a history of steroid use just before the diagnosis of CMV reactivation; one patient was given prednisolone with cotrimoxazole for suspected pneumocystis pneumonia and another patient was treated with prednisolone for suspected paclitaxel-induced lung injury. The exact dose/duration of steroids was not available from the records. Two patients had hypothyroidism. Comorbidities which could have contributed to defects in immunity included HIV (3 patients, 18%) and type 2 diabetes mellitus in 3 patients (18%). Since HIV infection itself renders individuals at an increased risk of CMV reactivation due to immunosuppression, this could be considered a confounding factor. Diabetes mellitus leads to an increased risk of bacterial and fungal infections, but not necessarily CMV reactivation/infection.

Clinical presentations (during the episode of cytomegalovirus reactivation)

[Table 2] lists the symptoms with which patients presented during the clinical episode, when CMV reactivation was documented. However, it must be noted that these clinical presentations may/may not have been due to CMV reactivation alone, as in most of these situations, there was evidence of other infections as well.
Table 2: Clinical presentation of cytomegalovirus reactivation in patients with solid tumor malignancies (n=17)

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Other concomitant infections (based on positive culture/tests)

All the patients with CMV reactivation were admitted with some clinical manifestation of infection. Twelve out of the 17 patients (71%) had positive tests for other microbes (based on culture testing) besides the positive CMV test. Some of them had more than one body fluid specimen positive on culture testing. One patient had a positive blood culture, 5 patients had organism grown in bronchoalveolar lavage (BAL) fluid/sputum, 3 had stool culture positive, 4 patients had organism cultured on skin/soft tissue pus swab, 1 patient's peritoneal drain fluid tested positive, 1 patient had positive urine culture, and 1 patient had grown microbes in the aspirate from an intrabdominal collection. Three patients (18%) had concomitant positive galactomannan test. In these patients with coinfection, it was difficult to ascertain whether clinical manifestations were due to CMV or due to the coinfection or the combination.

At the time of CMV reactivation, 8 (47%) patients had neutropenia, i.e., absolute neutrophil count (ANC) <1500/mm3 and all these patients received granulocyte-colony stimulating factors (G-CSFs) till the recovery of the counts. Eleven (65%) patients had lymphocytopenia (absolute lymphocyte count <1000/mm3), while 12 (71%) patients had thrombocytopenia (platelet count <100,000/mm3).

Cytomegalovirus copy numbers and associated clinical manifestations/end organ involvement

CMV copy numbers in these patients at the time of clinical manifestation (before starting any anti-CMV therapy) ranged from 250 to 1,490,000 copies/ml. CMV DNA testing was done only when there was suspicion based on clinical findings, and was not done at baseline i.e. in patients without any suspicion of CMV infection. The decision to test for CMV DNA in most of these patients was taken either as part of the infective workup, when they were not responding to antibiotics (and antifungals in some cases) or if there was a suspicion of CMV disease with end organ involvement (based on clinical feature and/or findings on imaging). However, here it should be noted that in none of these patients was any invasive test done to prove CMV-related organ involvement.

Regarding clinical manifestations, 5 (29%) patients had fever alone (possibly CMV syndrome), 7 (41%) patients had clinical and radiological findings of pneumonia [Figure 1], 4 (24%) patients had associated diarrhea, 1 (6%) patient had clinical and radiological features of meningoencephalitis [Figure 2] and 1 (6%) patient had associated esophagitis. In the absence of proven invasive CMV disease (tissue biopsy testing), we could not directly label them as end-organ involvement. Moreover, many of these patients had associated coinfections; so, causality, i.e., establishing that the end organ manifestation was due to CMV was difficult to establish without any tissue diagnosis.
Figure 1: Computed tomography scan picture of a patient with cytomegalovirus infection and pneumonia

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Figure 2: Magnetic resonance imaging of brain of patient with clinical features of meningo encephalitis showing T2/fluid attenuated inversion recovery hyperintensity involving the bilateral temporal lobes, suspicious for viral encephalitis

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Treatment of cytomegalovirus

Ten of 17 patients (59%) were given treatment for CMV. All of them were treated with injection ganciclovir (at the dose of 5 mg/kg intravenously [IV] twice daily). One patient was later switched to oral valganciclovir. The median duration of treatment was 2 weeks (range, 1–3 weeks). Only 1 of these patients was given maintenance oral acyclovir (to prevent further reactivation) for 3 months, after completion of ganciclovir treatment. Three of these patients (who were treated with ganciclovir) died despite treatment (due to CMV and/or associated infections or other conditions). One patient was treated with IV acyclovir (for suspected meningoencephalitis) along with other antimicrobials (but did not receive ganciclovir) and later recovered.

Four of these 17 patients (24%) died just after the diagnosis of CMV DNA positivity/reactivation and therefore remained untreated for CMV. In 2 other patients (12%), only monitoring of CMV level was done, which returned to normal at <150 copies/ml in 2 weeks, without any anti-CMV therapy. However, these patients were treated with IV antibiotics and clinically responded. Monitoring of CMV DNA level was done in 13 patients and could not be done in 4 patients as they died immediately after diagnosis of CMV DNA positivity/reactivation. Monitoring was done with testing for CMV DNA in the peripheral blood specimen by RT-PCR and was done approximately once every week till either CMV DNA became undetectable (or <150 copies/ml) or there was further clinical deterioration and patient died.

Complications/side effects of CMV-directed therapy could not be ascertained by retrospectively reviewing the clinical records. Ten patients (59%) required intensive care unit (ICU) stay during the course of treatment.

Other concomitant treatment

All our patients were on some other antimicrobials (empirical or based on culture reports). All the 17 patients received broad spectrum IV antibiotics which included a variety of antibiotics such as cefoperazone-sulbactam, meropenem, amikacin, levofloxacin, colistin, teicoplanin, vancomycin, linezolid, clindamycin, and metronidazole. Twelve of these 17 patients (71%) received antibiotics based on culture reports (blood or the other body fluids). Seven patients (41%) received antifungals including voriconazole, fluconazole, and caspofungin; 3 of these patients had positive galactomannan test, 1 patient had grown candida in peritoneal fluid, and another patient had candida grown in BAL fluid. Three patients were already on anti-retroviral therapy. Another patient was started on acyclovir due to suspected meningoencephalitis; this patient did not receive ganciclovir.

Clinical outcome of patients

Overall, 10 patients (59%) recovered from this acute episode of illness, while 7 patients (41%) deteriorated and died due to CMV and/or associated infections and other conditions. Of the 10 patients who recovered from the acute episode of illness, 6 patients continued to receive cancer-directed treatment; 5 patients of carcinoma cervix had only the brachytherapy part of concurrent chemoradiation remaining, so they completed that. One patient was continued on palliative chemotherapy without any dose modification. Although these patients continued on their remaining treatment, exact delay/gap due to this acute episode of illness could not be ascertained from the records. Three patients had just completed their treatment. One patient's further chemotherapy was discontinued, as the patient had completed a significant part of the planned anticancer treatment and also had a very complicated course during all previous chemotherapy cycles.


  Discussion Top


We performed this retrospective analysis to understand the clinical spectrum of CMV reactivation in patients of solid malignancies, including the clinical presentation and course of illness. We cannot comment on the incidence of CMV reactivation in solid tumor patients as we routinely do not test for CMV virus in our patients with solid tumors. Other studies[6],[9] in the past have also reported that CMV reactivation in solid tumors is underreported/underestimated.

In our analysis of 17 patients, we found that CMV reactivation occurred in different solid malignancies, especially in patients on active treatment (chemotherapy/chemoradiotherapy). Occurence of CMV reactivation in patients of solid malignancies indirectly indicates the presence of immunosuppression in such patients, although it happens less commonly as compared to patients with hematological malignancies. These patients had varied clinical presentations, with fever being the most common clinical manifestation in 88% of cases. However, these symptoms cannot be solely attributed to CMV presentations, given the fact that most of these patients (12 of 17) also had coinfections with other microorganisms. In none of the patients was CMV detected from any other tissue/body fluid apart from blood, so to link the organ manifestations directly with CMV reactivation may not be entirely correct. Ganciclovir, which is the first-line treatment for CMV disease, was given to 10 patients (in one patient, it was later switched to oral valganciclovir). The important finding was that 10 of these 17 patients required ICU care and 7 of the 17 patients, i.e., 41% eventually died during the course of their acute infectious episode. Certainly, this morbidity and mortality may not be attributed solely to CMV reactivation, but it was undoubtedly one of the contributing factors. This rate of mortality and associated morbidity suggests that CMV testing should be done more often than is being currently practiced in solid malignancy patients. Of those who got cured and survived, only one patient was given prophylactic acyclovir to prevent further CMV reactivation. The role of this prophylaxis is hard to define, as we do not know the probability of second reactivation and efficacy of this prophylaxis.

Previous studies have also reported similar observations. Schlick et al.[9] in a retrospective analysis of CMV positive cases found that of 107 cases, 17 were solid malignancies, while rest 90 cases were of hematological malignancies. Among these solid malignancy patients, approximately 50% of patients had clinically relevant viremia, which required treatment.[1] In this study, 3 of 17 patients (18%) died. The reason for a greater number of deaths in our patients could be a bias as our patients had very complicated courses, including more coinfections and ICU requirement; CMV testing was possibly done only in the very sick patients with solid tumor malignancies. Another single center study that analyzed 107 patients with CMV disease, including 75 with solid cancer, reported a mortality rate of 61.3% in solid malignancy patients. In this study, the mortality rate in patients of hematological malignancies with CMV reactivation was 43.8%.[10] The wide variation in results from various studies reiterates the fact that the awareness of the need for testing for CMV infection in patients with solid tumors is not widespread and different institutes have varying experiences.

With this high morbidity and mortality in patients with CMV reactivation (with or without coinfections), it is very important to make an early diagnosis. The question is when to test solid tumor patients for CMV reactivation? Probably we should test for CMV DNA in solid malignancies in certain conditions like- when patients have fever of unknown origin despite all routine workup and investigations, patients with known risk for immunosuppression (i.e., exposed to prolonged course of steroids), associated comorbid conditions like HIV infection. Not every patient with positive CMV testing (>150 copy/ml of CMV, in our study) will develop clinical manifestations, so serial monitoring (once a week) of the CMV copy numbers should be done, as well as a close watch for the development of any clinical manifestations of CMV infection.

If a patient has both clinical features and CMV positivity, it would be prudent to start therapy against CMV, given the associated high morbidity and mortality. CMV infection can have varied clinical manifestations, from asymptomatic viremia to CMV mononucleosis syndrome with fever, to end organ manifestations like-CMV colitis, CMV hepatitis, CMV pneumonitis, CMV encephalitis and CMV retinitis.[4] It is important to diagnose and treat CMV reactivation early in its course, to reduce potential morbidity and mortality.

Ganciclovir (intravenously) and valganciclovir (orally) are the first-line treatment options for management of CMV infection.[11] Regarding duration of treatment, recommendations are to treat for at least 2 weeks or till the virus is undetected,[12] whichever period is longer. During treatment, monitoring of CMV viral load should be done at least once weekly using the same method which was used to detect CMV reactivation at baseline.[12] In our study too, we monitored CMV DNA load once weekly in most of our patients and found gradual reduction in copy numbers.

Our study had some limitations. It was a retrospective analysis, and we could not clearly establish the link between CMV viremia and the clinical manifestations, as many of the patients had coinfections. Furthermore, our sample size was small, and we would need a larger number of patients to accurately describe the clinical pattern and outcome.


  Conclusion Top


CMV reactivation and its clinical implications in solid malignancy patients are probably underreported. Given its clinical impact (i.e., associated high morbidity/mortality), it should be suspected, tested, and treated, if positive.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Ljungman P, Boeckh M, Hirsch HH, Josephson F, Lundgren J, Nichols G, et al. Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials. Clin Infect Dis 2017;64:87-91.  Back to cited text no. 1
    
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Emery VC. Investigation of CMV disease in immunocompromised patients. J Clin Pathol 2001;54:84-8.  Back to cited text no. 2
    
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Dupont L, Reeves MB. Cytomegalovirus latency and reactivation: Recent insights into an age old problem. Rev Med Virol 2016;26:75-89.  Back to cited text no. 3
    
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Heininger A, Haeberle H, Fischer I, Beck R, Riessen R, Rohde F, et al. Cytomegalovirus reactivation and associated outcome of critically ill patients with severe sepsis. Crit Care 2011;15:R77.  Back to cited text no. 4
    
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Hummel M, Abecassis MM. A model for reactivation of CMV from latency. J Clin Virol 2002;25 Suppl 2:S123-36.  Back to cited text no. 5
    
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Rolston KV. Infections in cancer patients with solid tumors: A review. Infect Dis Ther 2017;6:69-83.  Back to cited text no. 6
    
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Gudiol C, Aguado JM, Carratalà J. Bloodstream infections in patients with solid tumors. Virulence 2016;7:298-308.  Back to cited text no. 7
    
8.
Kuo CP, Wu CL, Ho HT, Chen CG, Liu SI, Lu YT. Detection of cytomegalovirus reactivation in cancer patients receiving chemotherapy. Clin Microbiol Infect 2008;14:221-7.  Back to cited text no. 8
    
9.
Schlick K, Grundbichler M, Auberger J, Kern JM, Hell M, Hohla F, et al. Cytomegalovirus reactivation and its clinical impact in patients with solid tumors. Infect Agent Cancer 2015;10:45.  Back to cited text no. 9
    
10.
Wang YC, Wang NC, Lin JC, Perng CL, Yeh KM, Yang YS, et al. Risk factors and outcomes of cytomegalovirus viremia in cancer patients: A study from a medical Center in Northern TAIWAN. J Microbiol Immunol Infect 2011;44:442-8.  Back to cited text no. 10
    
11.
Razonable RR, Humar A, AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplantation. Am J Transplant 2013;13 Suppl 4:93-106.  Back to cited text no. 11
    
12.
Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, et al. The Third International Consensus Guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation 2018;102:900-31.  Back to cited text no. 12
    


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