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Cytomegalovirus (CMV) Is a Highly Prevalent and Prevalence Ranging from 45% to 100%.1 a National Globally Distributed Virus

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Cytomegalovirus (CMV) Is a Highly Prevalent and Prevalence Ranging from 45% to 100%.1 a National Globally Distributed Virus Clinical focus Cytomegalovirus disease in immunocompetent adults Daniel Lancini ytomegalovirus (CMV) is an internationally ubiq- MB BS Summary Student1 uitous human herpes virus with a worldwide sero- Cytomegalovirus (CMV) is a highly prevalent and prevalence ranging from 45% to 100%.1 A national globally distributed virus. Helen M Faddy C BSc(Hons), PhD serosurvey in 2006 estimated that 57% of Australians CMV infection in healthy adults is usually asymptomatic Senior Research Fellow, 2 or causes a mild mononucleosis-like syndrome. Research and Development2 between the ages of 1 and 59 years were seropositive. While primary CMV infection is common in the general CMV disease causes significant morbidity and mortality Robert Flower in neonates and severely immunocompromised adults. PhD community, it is usually asymptomatic or causes a mild 3 Research Program Leader, mononucleosis-like syndrome. The viraemic phase is CMV disease can present with a wide range of Research and Development2 generally self-limiting in healthy adults, and is followed manifestations, with colitis being the most common. Chris Hogan by a lifelong bloodborne latent phase within peripheral The incidence of severe CMV disease in MB BS, BSc(Hons), FRCPA 4 immunocompetent adults appears to be greater than Medical Director, monocytes and CD34+ myeloid progenitor cells (Box 1). Pathology Services2 However, in certain circumstances CMV infection is previously thought, which may be partly due to immune dysfunction related to comorbidities such as kidney capable of producing severe, life-threatening disease, 1 School of Medicine, disease or diabetes mellitus. University of Queensland, including a wide range of potential clinical manifesta- CMV disease can mimic an array of alternative Brisbane, QLD. tions, owing to systemic haematogenous dissemination 2 Australian Red Cross 6 diagnoses and pose a significant diagnostic challenge, Blood Service, and a very broad tissue tropism (Box 2). Typically, severe especially in immunocompetent adults, leading to Brisbane, QLD. CMV disease occurs in the context of an immature, sup- delayed diagnosis, adverse health outcomes and daniel.lancini@ pressed or compromised immune system, and can lead unnecessary financial expense. 7 uqconnect.edu.au to death or permanent major sequelae. As such, severe Non-invasive testing for CMV is widely available and can CMV infection is a well recognised cause of morbidity facilitate early diagnosis if used appropriately. doi: 10.5694/mja14.00183 and mortality in neonates and immunocompromised Although limited, current evidence suggests that adults, such as pharmacologically immunosuppressed targeted antiviral therapy with ganciclovir or transplant recipients and patients with AIDS.7 valganciclovir is appropriate for severe CMV disease in immunocompetent adults. CMV disease in immunocompetent adults While CMV is a well recognised pathogen in neonates It should be noted that the definition of immunocom- and immunocompromised adults, the burden of CMV petency in this analysis, like most published reviews and disease in immunocompetent adults is less well under- case reports, excluded only individuals with profound stood. This is because severe CMV disease is of consider- loss of immune function, including patients who had ably lower incidence in this population. However, it is far AIDS, pharmacologically immunosuppressed transplant from non-existent; over 380 published case reports docu- recipients and chemotherapy recipients. However, many ment instances of severe tissue-invasive CMV infection case reports of CMV disease in “immunocompetent” in immunocompetent adults. Similarly to CMV disease adults document comorbidities that may be associated in immunocompromised individuals, these cases show a with a degree of immune dysfunction, such as diabetes wide range of manifestations, including colitis,9 vascular mellitus or renal failure. Indeed, studies have also shown thrombosis,10 pneumonia11 and myocarditis.12 an increased risk of CMV-related morbidity and mortal- The most comprehensive evaluation of severe CMV ity in “immunocompetent” critically ill patients.13 It is infection in immunocompetent adults to date included therefore highly feasible that partial immune dysfunc- a systematic meta-analysis of case reports and reviews documenting 290 instances, across all manifestations.8 tion may represent a currently overlooked risk factor for This study found that CMV infection most commonly severe CMV disease. As such, further studies are needed involved the gastrointestinal tract (primarily colitis), to evaluate the risk of CMV disease in these populations. followed by the central nervous system (including men- Nonetheless, this possibility reinforces the importance ingitis, encephalitis and myelitis) and then haematologi- of considering CMV as a potential infectious agent even cal abnormalities (including haemolytic anaemia and in patients with a low degree of immune dysfunction. thrombocytopenia). CMV disease of the eye, liver, lung and vasculature were also documented, among other Diagnostic challenge of CMV disease conditions. The authors ultimately concluded that the incidence of severe manifestations of CMV infection in Although uncommon, severe CMV infection in immu- immunocompetent individuals appeared to be signifi- nocompetent adults often poses a significant diagnostic cantly more common than previously appreciated.8 challenge, and a number of case reports have documented 578 MJA 201 (10) · 17 November 2014 Clinical focus 1 Overview of primary and secondary cytomegalovirus 2 Non-exhaustive list of recognised potential (CMV) infection and disease4,5 manifestations of cytomegalovirus disease7,8 Direct eff ects Transmission Oral, sexual and Gastrointestinal Cardiovascular transplacental routes Asymptomatic Colitis Myocarditis Enteritis Venous thrombosis Primary infection Mononucleosis-like syndrome Gastritis Neurological Viraemia, multiorgan dissemination and shedding Hepatitis Meningitis Severely symptomatic Pancreatitis Encephalitis Potentially fatal or permanent complications Cholangitis Myelitis Seroconversion Detectable anti-CMV IgG Respiratory Retinitis Pneumonitis Uveitis Haematological Urological Viral clearance Thrombocytopenia Nephritis Neutralising Ig terminates viraemic phase Leukopenia Prostatitis Anaemia Disseminated intravascular Latent infection CMV resides in monocytes coagulation Secondary infection and CD34+ myeloid Myelodysplastic change progenitors, with lifelong Reactivation or reinfection seropositivity Indirect eff ects Atherosclerosis acceleration Accelerated AIDS progression Graft dysfunction and rejection Increased opportunistic considerable delay to diagnosis.14-16 Some patients with infections CMV colitis, in particular, have had protracted hospi- talisations and have undergone surgery to investigate commenced. The authors concluded that CMV should persistent and undiagnosed disease. be considered as a potential aetiological agent of severe The diagnostic difficulty in CMV disease arises from colitis in immunocompetent individuals when other dif- three factors. First, the low incidence of severe CMV dis- ferentials have been excluded.15 ease in immunocompetent individuals warrants a lower A case study by Falagas and colleagues highlighted index of clinical suspicion for CMV infection at initial the diagnostic difficulty posed by CMV disease in presentation. Second, CMV disease can present with a non-immunocompromised adults.14 In this instance, a wide array of potential clinical manifestations, owing to 57-year-old, HIV-negative man with chronic renal failure broad tissue tropism. Third, certain presentations of CMV presented with acute abdominal pain, diarrhoea, and disease strongly mimic other diseases, potentially causing per rectal bleeding. Colonoscopy showed a large poly- diagnostic confusion and delay in diagnosis. Indeed, case poid mass in the hepatic flexure, suspicious for colorectal studies have documented initial misdiagnoses of colon carcinoma, although a colonic biopsy specimen did not carcinoma,14 ischaemic colitis,15 inflammatory bowel dis- show neoplastic changes. The results of subsequent CT ease,16 dengue fever17 and lung cancer,18 among others. scanning, stool examination and a C. difficile toxin assay were normal. Recurrent symptoms prompted an explora- Notable case studies tory laparotomy and right hemicolectomy on Day 9 of admission, at which time histological analysis showed Siegal and colleagues documented the case of an 82-year- intranuclear inclusions diagnostic of CMV disease. The old man presenting with a 2-day history of diarrhoea and patient commenced a 2-week course of IV ganciclovir, epigastric pain.15 Non-contrast computed tomography and his symptoms subsequently abated. The authors (CT) showed faecal impaction and thickening of the wall concluded that the endoscopic findings of CMV colitis of the distal colon, with generalised large-bowel dilata- may resemble colon carcinoma and should be considered tion. Despite repeated negative results from assays for as a differential diagnosis, even in patients without severe Clostridium difficile toxin, antibiotics were administered. immunosuppression.14 There was no clinical improvement. Sigmoidoscopy and Yu and colleagues published a case report of a 39-year- biopsy during the second week of admission showed acute old woman with a 6-week history of fever of unknown inflammation and lymphoid aggregates, but did not lead origin who was referred to a tertiary hospital.19 Her
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