key: cord-0725279-rwpbbioz
authors: Díaz, A.; Zaragoza, R.; Granada, R.; Salavert, M.
title: Acute viral infections in immunocompetent patients
date: 2011-12-31
journal: Medicina Intensiva (English Edition)
DOI: 10.1016/s2173-5727(11)70023-6
sha: 8b20cfb9a760d4a1a8a5ca8e28bd68db4d32eb78
doc_id: 725279
cord_uid: rwpbbioz

Abstract Viruses play a significant role in serious infections in adults and sometimes lead to the need for hospitalization and admission to intensive care units, especially in cases of severe respiratory distress or encephalopathy. Influenza and parainfluenza viruses, syncytial respiratory virus, herpes viruses and adenovirures are the most frequent causes of these severe infections. A review of the literature has been performed in order to update the epidemiology, pathogenesis and therapeutic approach of viral infections affecting immunocompetent patients. Furthermore, ventilator-associated pneumonia (VAP) is the most frequent nosocomial infection in intensive care units and has a high morbidity and mortality rate. It is mainly a bacterial disease, although the potential role of viruses as pathogens or copathogens in VAP is under discussion. Therefore, a brief review of the potential pathogenic role of viruses in VAP has also been performed.

Septic processes remain one of the main causes of morbidity-mortality in ICUs throughout the world. In this context, viral infections cause many community-acquired infections in the general population and are also of great relevance in critical patients -particularly serious respiratory viral infections. 1 Among the causes of serious community-acquired pneumonia requiring hospital admission, viruses account for 15-40% of all cases in which the underlying etiology is known. 2

Viruses that invade through the airway can be grouped as follows: 

provided below of the main acute viral entities causing the most common serious respiratory disorders in immunocompetent adults, and which can be encompassed under the term "febrile respiratory illnesses (FRIs). 3 The causal viruses (Table 1 ) are grouped into two main categories: myxoviruses (including the different types associated with influenza A, B and C) and adenoviruses (involving 23 different types, of which 18 have been isolated in humans). Another parallel category corresponds to the parainfluenza viruses, of which a number of types are known. No description will be given here of the pneumonic conditions caused by HSV, VZV, EBV and CMV, as these have been described in the review corresponding to immune deficient patients.

The seasonal flu virus, the influenza virus, 4 

Severe acute respiratory syndrome (SARS) is caused by a recently manifesting RNA virus, coronavirus 6 (Coronaviridae), first described after an epidemic outbreak in 2003. The disease exhibits a biphasic clinical course with prodromic manifestations (fever, chills, muscle pain, nausea, headache) that progress within about 7-8 days to respiratory alterations with severe hypoxemia (in 45% of the cases), respiratory failure and ARDS (in 20%). The diagnosis is established by PCR and immunofluorescence, though viral cultures and ELISA can also be used. Treatment is fundamentally supportive, and in some cases corticosteroids can prove useful (following the development of ARDS). The reported mortality rate is about 11%, and is greater in patients over 65 years of age. Transmission is via droplets, the aerial route and contact. The clinical picture is characterized by prodromic manifestations (fever, chills, muscle pain, abdominal pain) and rapid progression towards respiratory failure, ARDS, coagulopathy and shock. The diagnosis is based on serological tests. Treatment comprises supportive measures and the administration of ribavirin in HFRS (not effective in HCPS). Transmission is through contact with the urine or excrements of infected mice.

1. Hemorrhagic fever conditions: Most of the diseases associated with hemorrhagic exanthema are caused by arboviruses (belonging to the families Alphaviridae and Flaviviridae). Of special mention in this group are the viruses that cause yellow fever (a biphasic condition characterized by an onset with fever, remission and reappearance with systemic bleeding, liver failure, gastrointestinal disorders and exanthemas -being endemic to equatorial Africa, equatorial America, and areas of the Caribbean and Asia) and dengue (the most important insect transmitted disease in humans, with acute manifestations involving fever, headache, nausea and vomiting, maculopapular exanthema, muscle pain and joint pain), and the Ebola and Marburg viruses (both 

Recent advances in virological diagnosis have resulted in substantial improvements in viral culture yield and rapidity (shell-vial assays), increased sensitivity and specificity of viral antigen detection techniques, an expansion of the available serological techniques, and particularly advances in the methods based on nucleic acid amplification procedures such as polymerase chain reaction (PCR). The most widely used diagnostic techniques 9 in the main clinical conditions are reported in Table 2 .

The currently available antiviral agents (Table 3) belong to two groups, according to their mechanism of action. On one hand, amantadine and rimantadine act upon protein M2 of the influenza A virus, inhibiting its capacity to lower the endosomal pH -this being essential in order to destroy the viral envelope and release the nucleocapside. Amantadine is effective against influenza A virus, but not against influenza B virus (the latter lacks protein M2, and instead has a substituting protein called NB that is not affected by amantadine). On the other hand, oseltamivir (Tamiflu ® ) and zanamivir (Relenza ® ) block the active site of neuraminidase, thus preventing the spread of the virus. These drugs have demonstrated activity against the influenza A and B viruses.

Among the supportive measures common to the treatment of many of these diseases (Table 1) , mention must be made of appropriate oxygen therapy, corticosteroids and aerosol therapy (bronchodilators, corticosteroids or ribavirin). The non-pharmacological management 3 of critical patients with serious febrile respiratory illness varies according to the implicated infectious agent (suspected or confirmed) and the severity of the respiratory condition -though most cases present clinical similarities allowing us to establish a certain management pattern. Thus, in all cases intensive supportive measures are necessary (fluids, amines, renal replacement therapy), such as those used in septic shock of other origins. These patients usually suffer serious lung injuries, thus leading to the need for mechanical ventilation. In cases where ARDS has developed, protective strategies must be applied to mechanical ventilation (low tidal volume [6 ml/ kg], high PEEP values to reduce atelectasic areas). The more milder cases sometimes respond favorably to early noninvasive ventilation (NIV), though there is controversy over the use of this technique in such patients.

Although the etiology of ventilator-associated pneumonia (VAP) has always been classified as bacterial, that fact is that at present episodes are recorded in which the etiology h as n ot be e n de fin e d. Pa rt icu la rly following t he introduction of highly sensitive techniques for the detection of viruses in the respiratory tract, studies have been published in the last decade pointing to a possible role of viruses in the pathogenesis of these important infections that are especially prevalent in ICUs. Although to date no regular diagnostic standard has been established, none of these publications have established a causal relationship between isolation and the infectious episode; moreover, there is no evidence from studies or clinical trials on the role of antiviral agents in these purportedly viral processes.

A French prospective study 10 conducted in a university hospital included all patients ventilated for more than 48 hours during a period of 9 months (n = 139). Tracheal aspirates were studied to detect the presence of viruses using different techniques, including PCR. The isolated viruses were rhinovirus, herpes simples, influenza, respiratory syncytial, enterovirus, parainfluenza, adenovirus, coronavirus and CMV, detected in 25% of the patients. No cases of attributable viral pneumonia were identified in the VAP episodes, though it must be mentioned that herpes simplex virus type I (HSVI) was isolated in 31% of the VAP episodes. Therefore, HSVI appears as the most likely implicated viral agent, as also suggested by a recent national series 11 and by several international studies published in the last decade. [12] [13] [14] [15] [16] The reported frequency varies between 5-64%, with a median of 15-20%. Although reactivation and CMV disease classically have been linked to patients with cellular immune alterations, 17 in the last decade reactivation also has been reported in immunocompetent critical patients. [18] [19] [20] [21] The incidence is variable, depending on the diagnostic method used (culture or PCR), and ranges from 12-33%. 18 In a recent study, 22 19% of the ventilated patients with suspected VAP yielded positive serological tests for Acanthomaeba polyphaga (though 64% of the episodes showed positivity in the BAL bacterial culture) -a mimivirus that had been previously associated to episodes of community-acquired and nosocomial pneumonia. 23

The reactivation of a latent virus appears to be the initial mechanism in all patients with HSVI-caused pneumonia in the ICU. The existence of prior positive serological tests with the preceding presence of mucocutaneous lesions and/ or a positive pharyngeal smear in most episodes, confirms this point. 12, 16 Reactivation caused by instrumentation or trauma of the airway can occur in the oropharyngeal mucosa and upper respiratory tract, with posterior microaspiration towards more distal zones, or directly in the bronchial mucosa itself. 24 Reactivation starts between the third and fifth day of mechanical ventilation, reaching a peak in viral load after exponential expansion by day 12 (up to 10 8 copies/ml), 24 followed by a slow decline. Viral load has been correlated to the diagnosis of viral bronchopneumonitis.

The most frequent risk factors [12] [13] [14] [15] [16] 25 for HSVI infections of the lower respiratory tract have been the presence of mucocutaneous herpetic lesions, a positive pharyngeal smear, tracheal mucosal lesions, thrombocytopenia, high SOFA and/or APACHE II scores, mechanical ventilation for over 7 days, old age, the use of corticosteroids during admission to the ICU, and HSVI IgG positivity upon admission.

As has been mentioned, the reactivation of CMV is frequent in the critical patient, and occurs between days 14 and 21 of stay in the ICU. [18] [19] [20] [21] Reactivation may begin in the lung parenchyma 25 activated by sepsis, as has been demonstrated in animal models involving latent CMV infection, and can cause a persistent increase in cytokinemediated inflammatory response. 26 The risk factors described for active CMV infection in immunocompetent patients subjected to mechanical ventilation are blood transfusion, previous hospitalization, age and prior corticosteroid use. 20 In the only clinical study published on mimivirus and VAP, the risk factors associated to positive serology testing for this virus were the duration of mechanical ventilation prior to bronchoalveolar lavage, the detection of no other viruses, and the absence of enteral nutrition. 22

The role of HSV as a cause of lower respiratory tract infection remains to be defined, and isolation of the virus may correspond to contamination from the upper respiratory tract, mucosal viral excretion or bronchopneumonitis, since over half of the cases of purported viral VAP show coexisting bacterial isolation 12, 24 ; accordingly, isolation may simply be a severity marker or may reflect the existence of a pathogen in its own right. 27 A number of studies have attempted to document the true incidence of VAP caused by CMV. 20, 25, 28 A total of 29.4% out of 85 patients diagnosed with ARDS with suspected VAP and with negative culture results had histopathological findings compatible with CMV pneumonia 25 in a study published in 1996. Eleven years later, these same authors, based on in vivo biopsies in a population of 100 patients, demonstrated a high incidence of CMV pneumonia (30%) and a low diagnostic yield for both PCR and BAL sample culture (sensitivity 53% and specificity 92%). 28 In a recent study, the incidence of active CMV disease was found to be high in a series of 242 immunocompetent patients subjected to ventilation for over 48 hours (16.1%) . 20 In view of the above, CMV should be suspected as the cause of VAP in the presence of persistent infiltrates, a lack of clinical improvement and negative bacterial cultures -using PCR to evaluate the possibility of CMV reactivation. Antiviral therapy should be started, and where necessary, confirmation of the diagnosis may be established by lung biopsy.

Patients infected with HSV require longer mechanical ventilation and hospital stay, though no studies have been able to demonstrate an increase in mortality. 12, 13, 16, 24 No data from adequate studies are available to allow the recommendation of antiviral treatment in cases of HSV infection, though clinical trials are clearly needed given the growing incidence of these infections and their association to longer stays and mechanical ventilation, since patient benefits could be derived as a result.

In a previously cited study evaluating the incidence, risk factors and prognosis of patients with active CMV disease, 20 the latter was seen to be associated to longer stays, more days on mechanical ventilation, and an increase in the number of nosocomial infections compared with patients without active CMV disease. Mortality both in the ICU (54% versus 37%; p = 0.082) and in hospital (59% versus 41%; p = 0.058) was higher in the CMV disease group, with an important tendency towards statistical significance. In the multivariate analysis, active disease was found to be independently associated to mortality in the ICU, along with the APACHE II score. Table 4 summarizes the main characteristics of VAP of 

High prevalence of respiratory viral infecions in patients hospitalized in an Intensive Care Unit for acute respiratory infections as detected by nucleic acid-based assays

Viral infection in adults hospitalized with community-acquired pneumonia

Severe Febrile Respiratory Illnesses as a cause of mass critical care

Respiratory Syncytial Virus and Parainfluenza Virus

Severe acute respiratory syndrome (SARS): A critical care perspective

Acute febrile respiratory illness in the ICU

Bench-to-bedside review: Rare and common viral infections in the intensive care unit-linking pathophysiology to clinical presentation

Role of the laboratory in diagnosis of influenza during seasonal epidemics and potential pandemics

Nosocomial viral ventilator-associated pneumonia in the intensive care unit: a prospective cohort study

on behalf of The Gregorio Marañón Task Force for Pneumonia. Herpes simplex virus: A marker of severity in bacterial ventilator-associated pneumonia

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Herpes simplex type 1 shedding is associated with reduced hospital survival in patients receiving assisted ventilation in a tertiary referral intensive care unit

Occult herpes family viral infections are endemic in critically ill surgical patients

Herpes simplex virus load in bronchoalveolar lavage fluid is related to poor outcome in critically ill patients

Monitoring of herpes simplex virus in the lower respiratory tract of critically ill patients using realtime PCR: a prospective study

Major trends in nosocomial viral infections

Cytomegalovirus reactivation in critically ill immunocompetent patients

Prevalence and mortality associated with cytomegalovirus infection in nonimmunosuppressed patients in the intensive care unit

Active cytomegalovirus infection is common in mechanically ventilated medical intensive care unit patients

A silent killer: cytomegalovirus infection in the nonimmunocompromised critically ill patient

Clinical significance of a positive serology for mimivirus in patients presenting a suspicion of ventilator-associated pneumonia

Mimivirus in pneumonia patients

Herpes simplex virus lung infection in patients undergoing prolonged mechanical ventilation

An unexpected cause of ventilatorassociated pneumonia

Pulmonary cytomegalovirus reactivation causes pathology in immunocompetent mice

Vandenbroucke-Grauls CM. Herpes simplex virus type 1 and respiratory disease in critically-ill patients: Real pathogen or innocent bystander?

A contributive result of open-lung biopsy improves survival in acute respiratory distress syndrome patients