Cough and shortness of breath in a noncompliant patient with HIV/AIDS.
What was the cause of the fatal respiratory failure in this case?
Answer on p. 203
Diagnosis: Cytomegalovirus pneumonia
Cytomegalovirus (CMV) is a member of the beta herpes virus subfamily which also includes human herpes viruses 6 and 7. The name has a Greek etiology from the word herpein which means to creep and alludes to the virus' characteristic dormancy and recurrent reactivating infections. It is composed of a double stranded DNA genome, approximately 230 kb in size and is the largest among the known human viruses. CMV was first detected in the early 1900s when multiple reports described large cells in the urine of children with a fatal systemic infection that was accordingly referred to as cytomegalic inclusion disease. (1) Since this time, and in particular over the past two decades, both detection methods as well as therapeutic regimens targeting CMV have notably advanced albeit without a significant decrease in the CMV-associated morbidity, mortality and healthcare associated costs, particularly in the immunocompromised host.
CMV is the most common congenital viral infection, with nearly 40,000 new cases yearly in the US and an overall incidence of 1-2.4 percent of all live births. (1,2) CMV can also be acquired in the neonatal period through breast feeding but with a wide variability in both transmission rates (6-60 percent) as well as disease rates (0-35 percent). (1,3) CMV has also been transmitted sexually and via both blood transfusions as well as solid organ transplantation. All transmission routes combined, CMV's overall seroprevalance rate ranges from 60-80 percent in developed nations to nearly 100 percent in developing countries; and most individuals seroconvert before the age of 40 years. (4)
Primary CMV infection in the immunocompetent patient is frequently asymptomatic but occasionally there is a mononucleosis-like prodromal illness which resolves untreated within a few weeks. However, like all human herpes viruses, CMV establishes a lifelong latency following the primary infection that can periodically reactivate with viremia or viral shedding in various body fluids including saliva, urine, tears, semen, cervicovaginal fluid and breast milk. (3) In 20 percent of the perinatal cases, there are permanent sequelae the most common of which is sensorineural hearing loss. (1) Other congenital manifestations include microcephaly, mental retardation, paralysis, anemia, and optic nerve atrophy leading to blindness.
A growing body of literature describes severe CMV-related disease in the immunocompromised host. In solid organ transplant recipients, CMV infection is an independent risk factor for organ rejection and nearly one-third of patients develop end-organ disease in the transplanted organ within the first three postoperative months. (5) In bone marrow transplant patients, CMV infection carries an 80 percent mortality rate if untreated. (1,6) And, among HIV infected patients, those who are CMV seropositive progress more rapidly to AIDS and an overall shorter survival rate than those who are seronegative. (7) Further, primary CMV tends to occur far more commonly in the advanced HIV positive patient, who has CD4+ counts below <50 cells/mm3, high viral loads (>100,000 copies/ml) and either concomitant or prior opportunistic infections and in those with other comorbidities such as diabetes. (8)
In the HIV/AIDS population, a great number and variety of effects and sequelae of CMV have been described and include gastrointestinal disease, hepatitis, encephalitis, pneumonia and retinitis. CMV as an independent risk factor for mortality in the untreated HIV population has also been supported by several large scale studies where death rate is logarithmically associated with copy numbers of CMV DNA. (9) In cohorts who are compliant with antiretroviral therapy, however, there is current evidence to suggest not only reduced rates of CMV infectivity but also a less severe spectrum of disease. (1,6) CMV pneumonia in the HIV population has been studied extensively in the autopsy literature. (10,11) In two fairly large studies of 75 and of 54 HIV-associated autopsies, histologic evidence of CMV was found in approximately 50 percent of cases. (11,12) In these series, the lung was the most common organ affected; although widespread dissemination was also documented in 59 percent of cases. CMV was found both as a single isolate as well as in combination with other pathogens such as Cryptococcus and Mycobacterium. The clinical cause of death in 80 percent of cases with CMV was determined to be respiratory failure. Antemortem studies on CMV and HIV have also been undertaken; and bronchoalveolar lavage data suggest that CMV can be documented in up to one-half of all HIV patients with respiratory symptoms. But, neither the clinical picture nor the 3-week mortality rates in these infected patients was more severe than was seen in CMV-negative HIV patients. (13) As such, despite a growing body of literature that supports a pathogenic role of CMV in the HIV patient population, questions remain and are centered on whether its presence justifies a specific antiviral therapy and, if so, whether current diagnostic techniques are sufficient enough for early detection.
The preferred laboratory diagnosis of CMV hinges on the bronchoalveolar lavage (BAL) sample. Various techniques are then employed including routine culture, serology, histopathology, antigen stains and molecular amplification. While traditional viral culture may take up to 21 days to produce a positive result and serology is inherently insensitive and difficult to interpret particularly in the immunocompromised host, the current approach for diagnosing CMV infection in the HIV population relies primarily on histopathology, rapid antigenemia assays and PCR amplification methods. (14)
The microscopic pathology of CMV infected cells, known as its viral cytopathic effect, is quite characteristic and can be well appreciated in Figure 1. The infected cell becomes enlarged and an intranuclear, round to oval, often basophilic inclusion measuring up to 20-40 microns is seen. There is a peripheral halo around the inclusion and accentuation of the surrounding nuclear membrane. Following Ganciclovir therapy, the intranuclear inclusion of CMV is said to take on a more globular and eosinophilic appearance indicative of a treatment effect. Cytoplasmic inclusions have also been seen in infected cells, though less distinct and smaller, often measuring only 1-3 microns but more readily apparent with special stains such as periodic acid-schiff (PAS) and gomori-methenamine silver (GMS). For cases wherein routine histopathology is not pathognomonic, either immunohistochemistry or in situ hybridization may be undertaken. CMV infected lung tends to demonstrate its characteristic viral cytopathic effect within not only the epithelial cells lining the airways but also within endothelial cells and intraalveolar macrophages. The four major histopathologic patterns of CMV lung infection are the (1) miliary or nodular pattern with an exuberant intra-alveolar fibrinopurulent exudate, (2) the diffuse interstitial form with features of diffuse alveolar damage and interstitial edema, (3) a hemorrhagic form with diffuse recent hemorrhage, and finally (4) the bland, noninflammatory pattern with minimal evidence of lung pathology. (15)
The current case with its associated pathology image illustrates the typical clinical course and microscopic features of CMV pneumonia in an individual affected with HIV/AIDS. The patient was in the advanced stages of HIV/AIDS complicated by dialysis dependent nephropathy, a history of other opportunistic infections, and documented noncompliance with prescribed antiretroviral therapy. The histologic miliary-type pattern of acute pneumonitis and the added finding of CMV inclusions in the pancreas also suggest hematogenous spread and dissemination of CMV in this patient. Ultimately, the clinical cause of death was respiratory failure which was determined, by autopsy, to be due to CMV pneumonia. Considering the frequency with which CMV is detected in the HIV/AIDS population, additional attention is warranted, in particular to CMV pneumonia, such that a clinical consensus regarding not only its pathogenic significance but also regarding useful potential therapies can be achieved.
Reggie Thomasson, MD; Tracy Dewenter, MD; Robin R. McGoey, MD
(1.) Boeckh M, Geballe AP. Cytomegalovirus: pathogen, paradigm, and puzzle. J Clin Invest. 2011;121:1673-1680.
(2.) Vancikova Z, Dvorak P. Cytomegalovirus infection in immunocompetent and imunocompromised individuals--a review. Curr Drug Targets Immune Endocr Metabol Disord. 2001;1:1:179-187.
(3.) Cannon MJ. Congenital cytomegalovirus (CMV) epidemiology and awareness. J Clin Virol. 2009 ;46:S6-S10.
(4.) Griffiths PD, Grundy JE. Molecular biology and immunology of cytomegalovirus. Biochem J. 1987;241:313-324.
(5.) Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013;45:260-271.
(6.) Rafailidis PI, Mourtzoukou EG, Varbobitis IC, et al. Severe cytomegalovirus infection in apparently immunocompetent patients: a systematic review. Virol J. 2008; 5:47.
(7.) Deayton JR, Sabin CA, Johnson MA et al. Importance of cytomegalovirus viraemia in risk of disease progression and death in HIV-infected patients receiving highly active antireteroviral therapy. Lancet. 2004;363:2116-2121.
(8.) Erice A, Tierney C, Hirsch M et al. Cytomegalovirus and human immunodeficiency virus burden, CMV end organ disease and survival in subjects with advanced HIV infection (AIDS Clinical Trials Group Protocol 360). Clin Infect Dis. 2003;37:567-578.
(9.) Fielding K, Koba A, Grant AD et al. Cytomegalovirus viremia as a risk factor for mortality prior to antiretroviral therapy among HIV-infected gold miners in South Africa. PLoS One 2011;5:e25571.
(10.) Baughman RP. Cytomegalovirus: the monster in the closet? Am J Respir Crit Care Med 1997;156:1-2.
(11.) Wallace JM, Hannah J. Cytomegalovirus pneumonitis in patients with AIDS. Findings in an autopsy series. Chest. 1987;9:196-203.
(12.) McKenzie R, Travis WD, Dolan SA et al. The causes of death in patients with human immunodeficiency virus infection: a clinical and pathologic study with emphasis on the role of pulmonary diseases. Medicine. 1991;70:326-343.
(13.) Miles P R, Baughman RP, Linnemann CC. Cytomegalovirusin the bronchoalveolar lavage fluid of patients with AIDS. Chest. 1990;97:10721076.
(14.) Rodriguez-Barradas MC, Stool E, Musher DM et al. Diagnosing and treating cytomegalovirus pneumonia in patients with AIDS. Clin Infect Dis. 1996(23)76-81.
(15.) Roy, S. (2015, June). Pathology of cytomegalovirus infection. Retrieved from URL: June 2015 doi:http://histopathology-india.net/cmv.htm
Dr. Thomasson is a third year pathology resident, Dr. Dewenter is an Assistant Professor of Pathology and Dr. McGoey is an Associate Professor of Pathology and Residency Program Director in the Department of Pathology at Louisiana State University School of Medicine in New Orleans.
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|Title Annotation:||Pathology Image of the Month|
|Author:||Thomasson, Reggie; Dewenter, Tracy; McGoey, Robin R.|
|Publication:||The Journal of the Louisiana State Medical Society|
|Article Type:||Clinical report|
|Date:||Jul 1, 2015|
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