Active cytomegalovirus infection in patients with septic shock.
Cytomegalovirus cytomegalovirus (sī'təmĕg'əlōvī`rəs), member of the herpesvirus family that can cause serious complications in persons with weakened immune systems. (CMV CMV cytomegalovirus.
1. controlled mechanical ventilation
Cytomegalovirus (CMV) ) is a pathogen of emerging importance for patients with septic shock Septic Shock Definition
Septic shock is a potentially lethal drop in blood pressure due to the presence of bacteria in the blood.
Septic shock is a possible consequence of bacteremia, or bacteria in the bloodstream. . In this prospective study, 25 immunocompetent im·mu·no·com·pe·tent
Having the normal bodily capacity to develop an immune response following exposure to an antigen.
im CMV-seropositive patients with septic shock and an intensive care unit stay of [greater than or equal to] 7 days were monitored by using quantitative pp65-antigenemia assay, shell vial culture, and virus isolation. Within 2 weeks, active CMV infection with low-level pp65-antigenemia (median 3 positive/5 x [10.sup.5] leukocytes) developed in 8 (32%) patients. Infection was controlled within a few weeks (median 26 days) without use of antiviral therapy. Duration of intensive care and mechanical ventilation mechanical ventilation
A mode of assisted or controlled ventilation using mechanical devices that cycle automatically to generate airway pressure. were significantly prolonged in patients with active CMV infection. CMV reactivation reactivation
to become active after a period of quiescence or, as in bacterial and viral infections, latency.
cross reactivation was associated with concomitant herpes simplex virus Herpes simplex virus
A virus that can cause fever and blistering on the skin, mucous membranes, or genitalia.
Mentioned in: Conjunctivitis
herpes simplex virus reactivation (p = 0.004). The association between active CMV infection and increased illness could open new therapeutic options for patients with septic shock. Future interventional studies are required.
Sepsis and septic shock are defined as a clinical syndrome with severe inflammatory response (1). Despite the availability of antimicrobial, antifungal, and supportive therapies, septic shock is fatal for about one third of patients.
Cytomegalovirus (CMV) is a human [beta]-herpesvirus that has high seroprevalence seroprevalence Immunology The proportion of a population that is seropositive–ie, has been exposed to a particular pathogen or immunogen; the seropositivity of a population is calculated as the number of individuals who produce a particular antibody divided in adults. CMV disease predominantly occurs as an opportunistic infection opportunistic infection
An infection by a microorganism that normally does not cause disease but becomes pathogenic when the body's immune system is impaired and unable to fight off infection, as in AIDS and certain other diseases. in patients with severe immunosuppression immunosuppression
Suppression of immunity with drugs, usually to prevent rejection of an organ transplant. Its aim is to allow the recipient to accept the organ permanently with no unpleasant side effects. and rarely occurs in immunocompetent patients (2). Clinical diagnosis of CMV disease, without the use of virus diagnostics, is hampered by the fact that the clinical signs and symptoms are not very specific. Patients in intensive care units (ICUs) are rarely monitored for active CMV infection; therefore, the development of active CMV infection remains unrecognized in most critically ill patients.
During recent years, CMV has been discussed as an emerging pathogen emerging pathogen Public health Any pathogen that ↑ incidence of an epidemic outbreak Examples Cryptosporidium, E coli O157:H7, Hantavirus, multidrug resistant pneumococci, vancomycin-resistant enterococci. See Emergent disease. in critically ill patients who are not receiving immunosuppressive therapy; however, the incidence of active CMV infection is controversial (3,4), and not all centers detected active CMV infections in these patients (5-7). Among critically ill patients, the highest incidence of active CMV infection was in patients with septic shock (3). The causality of sepsis, consecutive CMV reactivation, and CMV-associated pulmonary disease is supported by a mouse model of murine murine /mu·rine/ (mur´en) pertaining to, derived from, or characteristic of mice or rats.
adj. CMV reactivation after cecal cecal /ce·cal/ (se´k'l)
1. ending in a blind passage.
2. pertaining to the cecum.
Of, relating to, or having the characteristics of the cecum. ligation ligation /li·ga·tion/ (li-ga´shun) the application of a ligature.
tubal ligation sterilization of the female by constricting, severing, or crushing the uterine tubes. and puncture (8,9). Many factors could stimulate CMV reactivation in patients with septic shock; e.g., proinflammatory cytokines Cytokines
Chemicals made by the cells that act on other cells to stimulate or inhibit their function. Cytokines that stimulate growth are called "growth factors. (10,11), transient immune paralysis (compensatory antiinflammatory response syndrome) (12), and drugs (13).
This pilot study investigated the incidence and the natural course of active CMV infection in patients with septic shock and different strategies for CMV monitoring. The study may stimulate future interventional trials aimed at preventing CMV-associated illness of patients with septic shock.
Patients and Methods
For 9 consecutive months, patients in the anesthesiologic ICU ICU intensive care unit.
intensive care unit
see intensive care unit.
ICU , University Hospital Ulm, Ulm, Germany, who had septic shock, were monitored for active CMV infection. We did not monitor patients who underwent splenectomy Splenectomy Definition
Splenectomy is the surgical removal of the spleen, which is an organ that is part of the lymphatic system. The spleen is a dark-purple, bean-shaped organ located in the upper left side of the abdomen, just behind the bottom of the , transplantation patients, or patients receiving immunosuppressive therapy. Also, patients who had been in ICU <7 days were excluded because CMV reactivation and CMV-associated illness were expected to develop with a time delay. To define septic shock, we used the criteria established by the American College of Chest Physicians/Society of Critical Care Medicine (14). Clinicians were not made aware of virologic results. To avoid exogenous CMV infections, transfusions were limited to filtered leukocyte-reduced blood products. The study was approved by the local ethics committee and was in accordance with the Helsinki Declaration; informed consent was obtained.
CMV monitoring was performed twice during the first week of the study and once a week thereafter until the patient was discharged from ICU. Quantitative pp65-antigenemia assay; shell vial culture; and viral isolation in leukocytes, urine, and bronchial bronchial /bron·chi·al/ (brong´ke-al) pertaining to or affecting one or more bronchi.
Relating to the bronchi, the bronchial tubes, or the bronchioles. aspirate as·pi·rate
To take in or remove by aspiration.
A substance removed by aspiration.
The removal by suction of a fluid from a body cavity using a needle. were performed as previously described (15). Briefly, pp65 antigenemia was determined in blood collected in EDTA EDTA: see chelating agents. tubes and subjected to dextran dextran /dex·tran/ (dek´stran) a high-molecular-weight polymer of d-glucose, produced by enzymes on the cell surface of certain lactic acid bacteria. sedimentation (1% dextran in phosphate-buffered saline). Duplicates of 5x[10.sup.5] leukocytes were placed onto glass slides, and the pp65 antigen-positive cells were evaluated by immunofluorescence Immunofluorescence
A technique that uses a fluorochrome to indicate the occurrence of a specific antigen-antibody reaction. The fluorochrome labels either an antigen or an antibody. assay (IFA Immunofluorescent assay (IFA)
A blood test sometimes used to confirm ELISA results instead of using the Western blotting. In an IFA test, HIV antigen is mixed with a fluorescent compound and then with a sample of the patient's blood. ) by using a mixture of 2 monoclonal mouse anti-pp65 antibodies (20:1; Virion virion
Entire virus particle, consisting of an outer protein shell (called a capsid) and an inner core of nucleic acid (either RNA or DNA). The core gives the virus infectivity, and the capsid provides specificity (i.e., determines which organisms the virus can infect). , Ruschlikon, Switzerland; Argene Biosoft, Viva Diagnostika, Hurth, Germany) and goat anti-mouse immunoglobulin (Ig) G (Dianova, Hamburg, Germany) conjugated conjugated
estrogens, conjugated Warning - Hazardous drug!
C.E.S. with fluorescein isothiocyanate (FITC FITC
fluorescein isothiocyanate; used as a fluorescent label for proteins, especially antibodies. ).
Leukocytes, bronchial aspirate, and urine were investigated by shell vial culture and viral isolation with human embryonic lung fibroblasts Fibroblasts
A type of cell found in connective tissue; produces collagen.
Mentioned in: Skin Grafting . Three days after infection, shell vial cultures were fixed with methanol and analyzed by IFA (anti-CMV immediate early antibody, Argene Biosoft, Viva Diagnostika; FITC-conjugated goat anti-mouse IgG, Dianova). Phase contrast microscopy Phase-contrast microscopy is an optical microscopy illumination technique in which small phase shifts in the light passing through a transparent specimen are converted into amplitude or contrast changes in the image. was used to analyze viral isolation for [greater than or equal to] 6 weeks. Cytopathic effects of various viruses were confirmed by using viral typing with IFA and monoclonal antibodies.
At the initial evaluation, the following antibodies were determined semiquantitatively by using ELISA ELISA (e-li´sah) Enzyme-Linked Immuno-Sorbent Assay; any enzyme immunoassay using an enzyme-labeled immunoreactant and an immunosorbent.
n. (Medac, Hamburg, Germany): CMV IgG, CMV IgM, and herpes simplex virus (HSV (Hue Saturation Value) A color space similar to HSB. See HSB.
HSV - hue, saturation, value ) IgG. Patients with antibody indices >1 were considered antibody positive.
The following values were regularly recorded: body temperature, heart rate, blood pressure, respiratory rate, need for mechanical ventilation, oxygen supply (Fi[O.sub.2]), urinary output, hemodiafiltration, partial pressure of oxygen in arterial blood, pH, leukocyte count, platelet count, serum bilirubin Bilirubin
The predominant orange pigment of bile. It is the major metabolic breakdown product of heme, the prosthetic group of hemoglobin in red blood cells, and other chromoproteins such as myoglobin, cytochrome, and catalase. , aspartate aminotransferase (AST (AST Computer, Irvine, CA) A PC manufacturer founded in 1980 by Albert Wong, Safi Quershey and Tom Yuen (A, S and T). It offered a complete line of PCs that sold through its dealer channel. ), C-reactive protein, and serum creatinine. The severity of organ failure over time was recorded by monitoring the most relevant organ functions (pulmonary, cardiovascular, hematologic hematological, hematologic
pertaining to or emanating from blood cells.
total and differential white cell counts, hematocrit estimation, erythrocyte count. , hepatic) and using the Sepsis-related Organ Failure Assessment Score (SOFA) (16). Impairment of the central nervous system was not evaluated (Glasgow Coma Scale Glas·gow Coma Scale
A scale for measuring level of consciousness, especially after a head injury, in which scoring is determined by three factors: amount of eye opening, verbal responsiveness, and motor responsiveness. ) because most patients received sedatives.
Statistical analysis was performed by using nonparametric tests (Fisher exact test, Mann-Whitney U test Mann-Whitney U test,
n.pr See test, Mann-Whitney U. ) and GraphPad Prism 3.02 software (GraphPad Software, San Diego, CA, USA). Significance level was set at p = 0.05.
Among 375 patients in ICU, 38 consecutive patients with septic shock were eligible, but 13 were excluded because of CMV seronegativity (n = 5), immunosuppressive therapy (n = 2), or ICU stay <7 days (n = 6). Thus, 25 CMV-seropositive patients with septic shock and an ICU stay [greater than or equal to] 7 days were enrolled in the study.
Active CMV Infection
During the first 2 weeks after onset of septic shock, active CMV infection was detected by sensitive quantitative pp65-antigenemia assay in 8 (32%) patients (15). Active CMV infection was also detected by shell vial culture in 4 of these patients (in bronchial aspirate for 3 patients and in urine for 1). For 1 patient for whom shell vial culture in bronchial aspirate was positive, shell vial culture was also positive in leukocytes. Initial detection of active CMV infection was delayed when using shell vial culture (detected 1, 11, 20, and 21 days after onset of septic shock) compared with pp65-antigenemia in the same patients (0, 7, 10, and 14 days). Overall, pp65-antigenemia was low (median 3 positive/5x[10.sup.5] leukocytes; range 1-17) and became nondetectable with no antiviral therapy (median 26 days after onset of active CMV infection; range 1-61 days). One patient died while CMV infection was still active.
CMV IgM antibodies were found in 2 (25%) of 8 patients with and 2 (12%) of 17 patients without active CMV infection, a difference that was not significant. Also the quantitative levels of CMV IgG and IgM antibodies did not differ between groups with and without active CMV infection (Table).
Characteristics of Patients with and without Active CMV Infection
Patient characteristics such as age, sex, primary disease, and severity of organ failure at time of entry into the study did not differ between patients with and without active CMV infection (Table). Hydrocortisone hydrocortisone (hī'drəkôr`tĭzōn'), another name for the steroid hormone cortisol, more especially used to refer to preparations of this hormone used medicinally. (200 mg/day) was given to patients in both groups; no differences between groups were noted in body temperature, leukocyte count, platelet count, serum creatinine level, serum bilirubin level, AST level, and C-reactive protein level. Systemic infection by gram-positive and gram-negative microorganisms was detected equally in both groups, and catecholamine catecholamine (kăt'əkôl`əmēn), any of several compounds occurring naturally in the body that serve as hormones or as neutrotransmitters in the sympathetic nervous system. treatment for cardiovascular dysfunction was similar for both groups.
Overall, the severity of sepsis-related failure of multiple organs, determined by SOFA score (16), did not differ between patients with and without active CMV infection; however, patients with active CMV infection required mechanical ventilation and ICU therapy for a longer time than did patients without active CMV infection (p = 0.0025) (Table). Although mortality rates were not significantly different between patients with and without active CMV infection (63% vs 35%; p > 0.05), the deaths occurred later (median 44 days after onset of septic shock, range 24-72 days) for patients with active CMV infection than for patients without (median 21 days, range 14-35 days) (p = 0.03).
The clinical course of patients with positive CMV shell vial culture in bronchial aspirate was associated with the longest duration of mechanical ventilation (47, 50, and 80 days) and of ICU stay (50, 71, and 87 days); however, because of the low number of cases, statistical analysis was not performed.
Other Viral Infections
All 25 patients were HSV seropositive seropositive /se·ro·pos·i·tive/ (-poz´i-tiv) showing positive results on serological examination; showing a high level of antibody.
adj. ; viral isolation in bronchial aspirate showed reactivation of HSV in 8 (32%) patients, thereby showing for the first time that HSV and CMV reactivation were associated (p = 0.004, Table) and occurred simultaneously (Figure). Active HSV infections developed without skin or mucosal rash (occult HSV infection). Because of the low number of cases, the clinical outcome of patients with active CMV, HSV, or CMV/HSV coinfection could not be further differentiated. Viral isolation in bronchial aspirate and urine did not detect additional opportunistic viral infections such as polyoma pol·y·o·ma
A small form of the papovavirus that contains DNA and is associated with the formation of various tumors in rodents. Also called polyoma virus.
Noun 1. BK virus and exogenous viral infections such as adenovirus adenovirus
Any of a group of spheroidal viruses, made up of DNA wrapped in a protein coat, that cause sore throat and fever in humans, hepatitis in dogs, and several diseases in fowl, mice, cattle, pigs, and monkeys. , respiratory syncytial virus respiratory syncytial virus (sĭnsĭsh`əl): see cold, common. , and parainfluenzavirus in any patient.
While CMV is well known as a cause of serious illness in immunosuppressed Immunosuppressed
A state in which the immune system is suppressed by medications during the treatment of other disorders, like cancer, or following an organ transplantation.
Mentioned in: Fifth Disease patients, it is now being discussed as a pathogen of emerging importance for patients with septic shock. Generally, active CMV infection is not recognized in such patients because critically ill patients are not routinely monitored for CMV infection.
CMV reactivation developed in one third of our patients within 2 weeks of onset of septic shock, as has been found in studies using a similar prospective study design (3,11). Diagnostic assays of different sensitivity, different patient groups, and study designs could account for discrepant dis·crep·ant
Marked by discrepancy; disagreeing.
[Middle English discrepaunt, from Latin discrep results obtained by other groups (5,10). Thus, onset of active CMV infection was detected later in the retrospective studies (4,17,18).
Active CMV infection in patients with septic shock was characterized by a low viral load and resolved within a few weeks without antiviral therapy. We hypothesize hy·poth·e·size
v. hy·poth·e·sized, hy·poth·e·siz·ing, hy·poth·e·siz·es
To assert as a hypothesis.
To form a hypothesis. that upon CMV reactivation, patients with septic shock could mount a protective antiviral immune response, which was different from the immune response of most patients after transplantations (19); however, this hypothesis remains to be confirmed.
In a previous study we compared different assays for CMV monitoring of patients with organ transplants and demonstrated equal sensitivity of our pp65 antigenemia assay and CMV PCR PCR polymerase chain reaction.
polymerase chain reaction
Polymerase chain reaction (PCR) of blood cells but lower sensitivity of shell vial culture, CMV PCR in plasma, and CMV mRNA detection by nucleic acid sequence-based amplification (15). Because of low viral loads, the incidence of active CMV infection could be easily underestimated by less sensitive assays for patients with septic shock, which was shown here in that shell vial culture in blood cells detected only 1 patient with active CMV infection. Less sensitive assays could have been also the problem of studies that failed to detect active CMV infection in critically ill patients (5-7). We assume that assays with sensitivity similar to that of our pp65-antigenemia assay (e.g., CMV PCR of blood cells) may be equally used for CMV monitoring of patients with septic shock, considering the results of patients who had received transplants (3,11,15).
Shell vial culture was more likely to detect active CMV infection in bronchial aspirate than in urine or blood cells. Pulmonary CMV infection may be relevant for patients with septic shock (8,20). Shell vial culture of urine was rarely positive for CMV in patients with septic shock, a finding which differed for patients having received a kidney transplant (21).
As expected, quantitative analysis of CMV IgG and IgM antibodies could not discriminate between patients with and without active CMV infection. CMV IgG antibodies were analyzed to identify patients with previous CMV infection (CMV-seropositive patients); however, diagnosis of active CMV infection by detection of CMV IgM antibodies or rising CMV antibody titers are no longer recommended when sensitive CMV monitoring by pp65antigenemia assay or CMV PCR are available because the information they provide is limited.
The clinical role of active CMV infection in patients with septic shock is an area of ongoing discussion (4). We demonstrated that active CMV infection is associated with prolonged ventilation time and ICU stay. Ventilation time and ICU stay were more prolonged in a subgroup of patients for whom shell vial culture in bronchial aspirate was positive. CMV infection was associated with pulmonary disease despite low pp65 antigenemia and self-limiting CMV infection. We suppose that immunopathologic mechanisms could contribute to CMV-associated illness (22) in addition to direct cytopathic effects of the infection (20). Association of tumor necrosis factor tumor necrosis factor
n. Abbr. TNF
A protein that is produced in the presence of an endotoxin, especially by monocytes and macrophages, is able to attack and destroy tumor cells, and exacerbates chronic inflammatory diseases. and pulmonary immunopathologic features of active CMV infection was recently confirmed in a mouse model showing murine CMV reactivation after cecal ligation and puncture (9).
Deaths occurred later for patients with active CMV infection than for those without active CMV infection. This finding could be the consequence of CMV-associated disease, as has been suggested (17). Although our study was not designed to clarify the causality between active CMV infection and increased illness, we argue that active CMV infection increases illness and not vice versa. In the mouse model of CMV reactivation, the causality between sepsis, CMV reactivation, and pulmonary disease has already been shown (9).
Recently, reactivations of HSV and human herpesvirus herpesvirus, any of the family (Herpesviridae) of common DNA-containing viruses, many of which are associated with human disease. See cytomegalovirus; Epstein-Barr virus; herpes simplex; herpes zoster. 6 have been reported in critically ill patients (7,23). We demonstrated for the first time an association between active HSV and CMV infection (p = 0.004). HSV was isolated from bronchial aspirate in the absence of skin and mucosal lesions, whereas other herpesviruses Herpesviruses
A family of viruses responsible for cold sores, chicken pox, and genital herpes.
Mentioned in: Skin Resurfacing , such as varicella-zoster virus, could not be isolated. The coincidence of HSV and CMV reactivation during the first 2 weeks of septic shock suggests a common trigger mechanism for herpesvirus reactivations. In future studies, more sensitive assays (e.g., PCR) may be used to analyze the incidence of other occult herpesvirus reactivations. Reactivation of polyoma BK virus, which commonly causes opportunistic infection after transplantation, was not detected by virus isolation. This finding leads to the hypothesis that the conditions that stimulate polyomavirus reactivation and those that stimulate CMV and HSV reactivation may differ. The absence of exogenous viral infection (e.g., adenovirus, respiratory syncytial virus, parainfluenzavirus) strengthens the suggestion that exogenous nosocomial nosocomial /noso·co·mi·al/ (nos?o-ko´me-il) pertaining to or originating in a hospital.
1. Of or relating to a hospital.
2. viral infections are uncommon in patients in ICUs (24). Thus, monitoring for viral infections could focus on endogenous herpesvirus reactivations in patients with septic shock. Immunosuppression and proinflammatory cytokines, drugs, or combinations are presumed to be involved in herpesvirus reactivations; however, the exact mechanisms are still elusive for patients with septic shock (13,25).
After organ transplants, CMV-associated illness and death could be reduced by early antiviral therapy; however, delayed therapy has been less effective (2). Anecdotal reports show that critically ill patients with already established CMV organ disease may not benefit from antiviral therapy (3,4,20). The effect of preemptive pre·emp·tive or pre-emp·tive
1. Of, relating to, or characteristic of preemption.
2. Having or granted by the right of preemption.
a. antiviral therapy or antiviral prophylaxis has not been tested so far in patients with septic shock; however, in the mouse model, prophylactic treatment with ganciclovir prevented murine CMV reactivation and CMV-associated pulmonary fibrosis (9).
Despite the low patient number in this and previous studies, we suggest that CMV is a pathogen of emerging importance that can no longer be ignored for patients with septic shock. Thus, interventional studies aimed at preventing CMV-associated illness in patients with septic shock are needed.
We thank everyone involved in diagnosis and treatment of the critically ill patients for their excellent assistance.
This study was supported by Roche Diagnostics, Mannheim, Germany. The funding source was not involved in the study design, collection, analysis, and interpretation of data, in the writing of the report, and in the decision to submit the manuscript for publication.
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Address for correspondence: Thomas Mertens, Department of Virology, University Hospital Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany; email: firstname.lastname@example.org
Lutz von Muller, * Anke Klemm, * Manfred Weiss, * Marion Schneider, * Heide Suger-Wiedeck, * Nilgun Durmus, * Walter Hampl, * and Thomas Mertens *
* University Hospital Ulm, Ulm, Germany
Dr von Muller is a senior researcher in the Department of Virology, University Hospital Ulm, Ulm, Germany. He specializes in pediatrics, microbiology, and epidemiology of infectious diseases. His main research interest is clinical virology and the role of antiviral immunity.
Table. Characteristics and clinical course of patients with septic shock, with and without active CMV infection * Active No active CMV CMV infection infection No. patients 8 17 CMV IgG, index 12.4 (5.4-14.7) 11.7 (1.5-18.3) CMV IgM, index 0.4 (0.28-3.94) 0.28 (0.2-1.8) Sex, n Male 5 10 Female 3 7 Age, y 66 (40-78) 60 (44-78) Primary condition, n Abdominal surgery 1 7 Abdominal tumor 1 4 Pancreatitis 3 1 Trauma 2 5 Vascular surgery 1 0 Bacteremia, n (%) 4 (50) 10 (59) Candidemia, n (%) 2 (25) 1 (6) SOFA score ([section]) 10 (7-13) 10 (7-16) Leukocyte count, g/L ([section]) 27 (10.4-53.3) 22.4 (7.2-74.3) Platelet count, g/L ([paragraph]) 106 (37-151) 112 (37-385) Serum creatinine, [micro]mol/L ([section]) 183 (73-345) 160 (72-347) Serum bilirubin, [micro]mol/L ([section]) 27 (6-279) 54 (4-336) Aspartate aminotransferase, U/L ([section]) 45 (9-229) C-reactive protein, mg/L ([section]) 258 (16-456) 220 (115-437) ICU stay after onset of septic shock, d 42 (16-87) 18 (10-42) Mechanical ventilation, d 39 (15-80) 16 (5-38) Receipt of catecholamines, d 7 (4-41) 7 (1-35) Mortality rate, n (%) 5 (63) 6 (35) HSV reactivation, n (%) 6 (75) 2 (12) Significance No. patients CMV IgG, index NS ([dagger]) CMV IgM, index NS ([dagger]) Sex, n Male NS ([double dagger]) Female NS ([double dagger]) Age, y NS ([dagger]) Primary condition, n Abdominal surgery NS ([double dagger]) Abdominal tumor NS ([double dagger]) Pancreatitis NS ([double dagger]) Trauma NS ([double dagger]) Vascular surgery NS ([double dagger]) Bacteremia, n (%) NS ([double dagger]) Candidemia, n (%) NS ([double dagger]) SOFA score ([section]) NS ([double dagger]) Leukocyte count, g/L ([section]) NS ([dagger]) Platelet count, g/L ([paragraph]) NS ([dagger]) Serum creatinine, [micro]mol/L ([section]) NS ([dagger]) Serum bilirubin, [micro]mol/L ([section]) NS ([dagger]) Aspartate aminotransferase, U/L ([section]) NS ([dagger]) C-reactive protein, mg/L ([section]) NS ([dagger]) ICU stay after onset of septic shock, d p = 0.00251 Mechanical ventilation, d p = 0.00251 Receipt of catecholamines, d NS ([dagger]) Mortality rate, n (%) NS ([double dagger]) HSV reactivation, n (%) p = 0.0036 ([double dagger]) * Median (range), unless otherwise indicated; CMV, cytomegalovirus; Ig, immunoglobulin; NS, not significant (p>0.05); SOFA, sepsis-related organ failure assessment, ICU, intensive care unit; HSV, herpes simplex virus. ([dagger]) According to Mann-Whitney U test. ([double dagger]) According to Fisher exact test. ([sectio]) Highest values. ([paragraph]) Lowest values.