Acute Respiratory Infection: First Clinical Manifestation of Active Infection with Cytomegalovirus in Hiv Patients Presenting to the Emergency Department

Introduction. Traditionally, digestive and ophthalmic symptoms have been described as predominant in the clinical presentation of active infection with cytomegalovirus (AICMV). Nevertheless, it seems that this has changed following the introduction of antiretroviral therapy (ART). Nowadays, respiratory infection (RI) in HIV-infected patients is the first reason for consulting an Emergency Department (ED). Among these patients, the mortality is important.


INTRODUCTION
Human cytomegalovirus (CMV) infection is highly prevalent in the world, especially in developing countries where 90% of the population is infected with this virus, while infection is estimated at 60% in developed countries.(1) In immunocompetent individuals, the infection is usually asymptomatic, mild or causes a mononucleosis syndrome but in immunosuppressed patients it behaves as an opportunistic pathogen, causing severe damage.(2) Specifically in HIV-infected patients with severe immune suppression, it manifests in up to 40% of them throughout their life, usually as ophthalmic manifestations or digestive.(3) However, following the introduction of combination antiretroviral therapy (cART), prognosis has improved, and consequently active infection with cytomegalovirus (AICMV) has decreased.(4) Respiratory infection (RI) is one of several indicators of AICMV, and the main cause for attending an Emergency Department (ED) in HIV-infected patients.Community-acquired pneumonia is the leading cause of death in these patients.(5) Although the incidence of RI has decreased, and its etiology has changed due to the introduction of cART, it has a non-negligible mortality and often requires admission to an intensive care unit (ICU).(6) The study objectives were to clarify, in a cohort of HIV-infected patients, if the usual clinical manifestations of AICMV have changed, and if RI has an important role in the presentation of AICMA, Furthermore, we wanted to find out which microorganisms cause it, and what the 30-day mortality is.

Design, setting, and population
This is a single-center retrospective study taking place during the course of nine years (2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015) and performed at our hospital which conducts annual monitoring of 5000 HIV-infected patients.All patients with HIV infection who attended our ED with respiratory symptoms and were diagnosed with AICMV were included.

Study protocol
AICMV was defined as the isolation of the virus or evidence of CMV replication, regardless of symptoms, by polymerase chain reaction (PCR); culture in any fluid or body tissue; and CMV disease, where the infected patient, besides virus replication, shows symptoms or signs of disease (viral syndrome or visceral involvement).(7,8) For the diagnosis of pneumonia, regardless of etiology, the criteria of the Infectious Diseases Society of America were applied.(9) Severe immunosuppression was defined as the presence of a CD4 count of less than 200 cells/µl in blood.

Measurements
The following epidemiological, clinical and laboratory variables were collected from patients: sex, age, previous opportunistic infections, associated comorbidities, route of HIV transmission, toxic habits, cART, number of CD4, CD8 lymphocytes and HIV viral load (VL) (prior to admission), coinfection with hepatitis C virus (HCV), target organ of CMV infection, presence of fever, need for mechanical ventilation (MV), number of total leukocytes, platelets, hemoglobin, liver profile, ICU admission, and 30-day mortality.
To determine the presence of pathogens, the results of blood cultures (Bactec 9240; Becton Dickinson), Gram stain and culture of respiratory samples, Ziehl-Neelsen stain and culture of mycobacteria, silver stain to detect P. jirovecii, and PCR to identify the presence of other respiratory viruses, were collected.For the diagnosis of CMV, viral culture of bronchoalveolar lavage (BAL) and CMV detection by real-time quantitative PCR (Q-CMV Real Time, Nanogen) in plasma, BAL and / or biopsy of the affected organ, were performed.

Statistical analysis
Categorical variables were expressed as frequencies and percentages, and continuous variables were expressed as mean and standard deviation.Results were considered statistically significant if the p-value was less than 0.05.To evaluate the relationship between quantitative variables, T-test for independent samples was used in normally distributed variables and U-Mann Whitney in those not normally distributed.The chi-squared was used to evaluate the relationship between qualitative variables.All statistical analyses were calculated using SPSS version 20.0 (Chicago, IL, USA).
Table1.Descriptive analysis of the HIV and active infection by cytomegalovirus (AICMV) population.

DISCUSSION
Lower respiratory tract infection is the most common infection in HIV-infected patients, and sometimes it is the first clinical manifestation of infection.(10) Our study confirms this and adds that this is also the case in AICMV.Pneumonia was the most common presentation of respiratory infection (31 cases) and the most common cause was P. jirovecii, unlike what was described in the literature previously, where the main bacterial etiology remains mainly at the expense of S. pneumonia.(11) In our series, there were only four bacterial isolates and among them S. pneumoniae was the only one.This is due to the degree of severe immunosuppression in our patients who had not started ART (because being infected with HIV was unknown before admission to ED), or because they were in the first 6 months of treatment, where ART had not yet reached its maximum effectiveness.Pulmonary involvement with CMV infection in the form of pneumonitis has a similar presentation to the one with P. jirovecii infection, which can lead to confusion and errors in treatment.(12) The patients with TB did not show any mortality in our series.However, this information should be taken with caution because our sample size is very small.Recent World Health Organization (WHO) studies also show that TB is responsible for up to one quarter of deaths of HIV-infected patients, especially when the infection is advanced.(13,14) The highest percentage of respiratory manifestations in HIV-infected patients with AICMV shows a change in clinical presentation.Until now, according to the data reported in the scientific literature, ocular and gastrointestinal manifestations are the ones seen most frequently.(15) In our series, despite the high number of patients with immunosuppression, it was surprising that no patient had retinitis, but this is consistent with previous studies that have shown a decrease in retinitis, caused by CMV, in the cART era.( 16) The overall mortality in this study was 18%, and the leading cause of death was respiratory infection (9%).Mortality was higher in patients admitted to the ICU, as in previous studies.( 17) Our work contrasts with the findings of Lichtner et al. (18) where cardiovascular and neurological events, attributed to immune dysfunction due to HIV / CMV coinfection, were the leading causes of death.CMV is an immunomodulatory virus which favors the appearance of opportunistic diseases, and the vast majority of HIV patients have a coinfection at some point in their life, leading to increased activation of the immune system, even if they are on cART, (19) with a consequent increase in mor-bidity and mortality.Early identification of CMV infection can prevent the onset of opportunistic infections.Based on the above, we believe that detection should be early, requesting, if there is any suspicion, diagnostic tests in the same HED and BAL since, as we have seen, higher viral load of CMV in BAL leads to increased mortality.

LIMITATIONS
Among the limitations of our study we emphasize that this is a single-center, retrospective study based on laboratory confirmation of CMV infection with a small number of cases.

CONCLUSION
In HIV patients, respiratory infection is the most common manifestation of AI-CMV, and is caused by opportunistic microorganisms, resulting in a 9% mortality.