Characteristics of human metapneumovirus infection in adults hospitalized for community-acquired influenza-like illness in France, 2012-2018: a retrospective observational study.

OBJECTIVES: To describe the prevalence, clinical features and complications of human metapneumovirus (hMPV) infections in a population of adults hospitalized with influenza-like illness (ILI). METHODS: This was a retrospective, observational, multicenter cohort study using prospectively collected data from adult patients hospitalized during influenza virus circulation, for at least 24 h, for community-acquired ILI (with symptom onset <7 days). Data were collected from five French teaching hospitals over six consecutive winters (2012-2018). Respiratory viruses were identified by multiplex reverse transcription polymerase chain reaction (RT-PCR) on nasopharyngeal specimens. hMPV + patients were compared with hMPV- patients, influenza+ and respiratory syncytial virus (RSV)+ patients using multivariate logistic regressions. Primary outcome was the prevalence of hMPV in patients hospitalized for ILI. RESULTS: Among the 3148 patients included (1449 (46%) women, 1988 (63%) aged 65 and over; 2508 (80%) with chronic disease), at least one respiratory virus was detected in 1604 (51%, 95% confidence interval (CI) 49-53), including 100 cases of hMPV (100/3148, 3% 95% CI 3-4), of which 10 (10%) were viral co-infection. In the hMPV + patients, mean length of stay was 7 days, 62% (56/90) developed a complication, 21% (14/68) were admitted to intensive care unit and 4% (4/90) died during hospitalization. In comparison with influenza + patients, hMPV + patients were more frequently >65 years old (adjusted odds ratio (aOR) = 3.3, 95% CI 1.9-6.3) and presented more acute heart failure during hospitalization (aOR = 1.8, 95% CI 1.0-2.9). Compared with RSV + patients, hMPV + patients had less cancer (aOR = 0.4, 95% CI 0.2-0.9) and were less likely to smoke (aOR = 0.5, 95% CI 0.2-0.9) but had similar outcomes, especially high rates of respiratory and cardiovascular complications. CONCLUSIONS: Adult hMPV infections mainly affect the elderly and patients with chronic conditions and are responsible for frequent cardiac and pulmonary complications similar to those of RSV infections. At-risk populations would benefit from the development of antivirals and vaccines targeting hMPV.

Clinical management of respiratory syndrome in patients hospitalized for suspected Middle East respiratory syndrome coronavirus infection in the Paris area from 2013 to 2016.

BACKGROUND: Patients with suspected Middle East respiratory syndrome coronavirus (MERS-CoV) infection should be hospitalized in isolation wards to avoid transmission. This suspicion can also lead to medical confusion and inappropriate management of acute respiratory syndrome due to causes other than MERS-CoV. METHODS: We studied the characteristics and outcome of patients hospitalized for suspected MERS-CoV infection in the isolation wards of two referral infectious disease departments in the Paris area between January 2013 and December 2016. RESULTS: Of 93 adult patients (49 male (52.6%), median age 63.4 years) hospitalized, 82 out of 93 adult patients had returned from Saudi Arabia, and 74 of them were pilgrims (Hajj). Chest X-ray findings were abnormal in 72 (77%) patients. The 93 patients were negative for MERS-CoV RT-PCR, and 70 (75.2%) patients had documented infection, 47 (50.5%) viral, 22 (23.6%) bacterial and one Plasmodium falciparum malaria. Microbiological analysis identified Rhinovirus (27.9%), Influenza virus (26.8%), Legionella pneumophila (7.5%), Streptococcus pneumoniae (7.5%), and non-MERS-coronavirus (6.4%). Antibiotics were initiated in 81 (87%) cases, with two antibiotics in 63 patients (67.7%). The median duration of hospitalization and isolation was 3 days (1-33) and 24 h (8-92), respectively. Time of isolation decreased over time (P < 0.01). Two patients (2%) died. CONCLUSION: The management of patients with possible MERS-CoV infection requires medical facilities with trained personnel, and rapid access to virological results. Empirical treatment with neuraminidase inhibitors and an association of antibiotics effective against S. pneumoniae and L. pneumophila are the cornerstones of the management of patients hospitalized for suspected MERS-CoV infection.

Clinical characteristics and outcome of respiratory syncytial virus infection among adults hospitalized with influenza-like illness in France.

OBJECTIVES: The aim of this study was to analyse characteristics and outcome of respiratory syncytial virus (RSV) infection in adults hospitalized with influenza-like illness (ILI). METHODS: Patients hospitalized with ILI were included in this prospective, multicentre study carried out in six French hospitals during three consecutive influenza seasons (2012-2015). RSV and other respiratory viruses were detected by multiplex PCR in nasopharyngeal swabs. Risk factors for RSV infection were identified by backward stepwise logistic regression analysis. RESULTS: A total of 1452 patients hospitalized with ILI were included, of whom 59% (861/1452) were >65 years and 83% (1211/1452) had underlying chronic illnesses. RSV was detected in 4% (59/1452), and influenza virus in 39% (566/1452). Risk factors for RSV infection were cancer (adjusted OR 2.1, 95% CI 1.1-4.1, p 0.04), and immunosuppressive treatment (adjusted OR 2.0, 95% CI 1.1-3.8, p 0.03). Patients with RSV had a median length of stay of 9 days (6-25), and 57% of them (30/53) had complications, including pneumonia (23/53, 44%) and respiratory failure (15/53, 28%). Fifteen per cent (8/53) were admitted to an intensive care unit, and the in-hospital mortality rate was 8% (4/53). Pneumonia was more likely to occur in patients with RSV than in patients with RSV-negative ILI (44% (23/53) versus 26% (362/1393), p 0.006) or with influenza virus infection (44% versus 28% (157/560), p 0.02). CONCLUSION: RSV is an infrequent cause of ILI during periods of influenza virus circulation but can cause severe complications in hospitalized adults. Risk factors for RSV detection in adults hospitalized with ILI include cancer and immunosuppressive treatment. Specific immunization and antiviral therapy might benefit patients at risk.

Viruses detected by systematic multiplex polymerase chain reaction in adults with suspected community-acquired pneumonia attending emergency departments in France.

UNLABELLED: Infectious agents associated with community-acquired pneumonia (CAP) are under-studied. This study attempted to identify viruses from the upper respiratory tract in adults visiting emergency departments for clinically suspected CAP. Adults with suspected CAP enrolled in the ESCAPED study (impact of computed tomography on CAP diagnosis) had prospective nasopharyngeal (NP) samples studied by multiplex PCR (targeting 15 viruses and four intracellular bacteria). An adjudication committee composed of infectious disease specialists, pneumologists and radiologists blinded to PCR results reviewed patient records, including computed tomography and day 28 follow up, to categorize final diagnostic probability of CAP as definite, probable, possible, or excluded. Among the 254 patients enrolled, 78 (31%) had positive PCR, which detected viruses in 72/254 (28%) and intracellular bacteria in 8 (3%) patients. PCR was positive in 44/125 (35%) patients with definite CAP and 21/83 (25%) patients with excluded CAP. The most frequent organisms were influenza A/B virus in 27 (11%), rhinovirus in 20 (8%), coronavirus in seven (3%), respiratory syncytial virus in seven (3%) and Mycoplasma pneumoniae in eight (3%) of 254 patients. Proportion of rhinovirus was higher in patients with excluded CAP compared with other diagnostic categories (p = 0.01). No such difference was observed for influenza virus. Viruses seem common in adults attending emergency departments with suspected CAP. A concomitant clinical, radiological and biological analysis of the patient's chart can contribute to either confirm their role, or suggest upper respiratory tract infection or shedding. Their imputability and impact in early management of CAP deserve further studies. CLINICAL TRIALS REGISTRATION: NCT01574066.

[An update on measles]. / Actualité de la rougeole.

Measles is a highly contagious infectious disease, which needs more than 95% worldwide vaccination coverage of 2 doses to be eradicated. Despite an important involvement of the WHO for massive immunization, goals have not bean reached, and outbreaks can occur at any time in many countries, including Western Europe. In France, 22,000 cases were identified between 2009 and 2011, mainly in infants and young adults, which are not or not enough vaccinated (one dose). In 2012, even though the number of cases has drastically decreased, the outbreak is still going on, especially in South of France. That is why every clinician needs to be concerned about the clinical manifestations of the disease, and its complications. Besides a febrile rash, measles is often responsible of pneumonia and biologic hepatitis in adults. Hepatitis does not seem frequent in children. Clinicians need to be aware of specific complications, like encephalitis in case of cellular immunodepression, high risk of pneumonia in pregnant women. In patients previously vaccinated, incidence of complications is the same but patients are not contagious. Even if measles diagnosis is clinical, blood confirmation by serology is recommended in France when possible. Outcome is mainly favourable, but measles is not well-tolerated with high levels of hospitalisation even without any complication. Vaccination is the only way to protect against it.

French 2010-2011 measles outbreak in adults: report from a Parisian teaching hospital.

We reviewed 80 adult cases of measles seen in a Parisian hospital during the French 2010-2011 outbreak. Fifty per cent had at least one complication: pneumonia and hepatitis were the most frequent. Forty per cent of hospitalized cases did not have any complications, suggesting clinically poor tolerance of measles in adults. The outcome was always favourable. Subjects were younger, were more often French nationals and had a higher socio-economic status than the overall population. This report suggests that immunity resulting from natural disease in patients from an area where the disease is endemic is protective in the long term.

[Acute cytomegalovirus infection revealing systemic lupus erythematosus]. / Infection aiguë à cytomégalovirus révélatrice d'un lupus érythémateux systémique.

Systemic lupus erythematosus (SLE) remains of unknown origin. Herpes viridae infections seem to play a role in the pathogenesis of this disease. We report a 31-year-old man who presented an acute cytomegalovirus (CMV) infection with persistent fever and myopericarditis as the presenting manifestation of SLE. This case report emphasizes a difficult differential diagnosis between SLE and an acute CMV infection and suggests a possible role of this virus in the pathogenesis of SLE.

Sensitivity and specificity of a rapid influenza diagnostic test in children and clinical utility during influenza A (H1N1) 2009 outbreak.

INTRODUCTION: The influenza A (H1N1) 2009 outbreak caused death and a disruption of public health services. Rapid influenza diagnostic tests (RIDT) could be helpful to ease the triage of patients and prevent an overload of emergency and laboratory facilities. OBJECTIVES: To compare the sensitivity and specificity of the Clearview Exact Influenza A&B test and real-time reverse transcription(RT)-PCR to detect influenza A (H1N1) 2009 in a paediatric emergency department of a paediatric teaching hospital in Paris, France. METHODS: 76 children with an influenza-like illness and either severe symptoms or an underlying medical condition were prospectively recruited between July 2009 and October 2009. RIDT and RT-PCR were simultaneously performed and compared. RESULTS: Among 39 influenza A (H1N1) 2009 RT-PCR-positive children (median age 5 years), 23 Clearview Exact Influenza A&B tests were positive. Sensitivity was 59% (95% CI 42.2 to 74) and specificity was 94.6% (95% CI 80.5 to 99.1). CONCLUSIONS: This study shows a sensitivity of RIDT of 59%, in agreement with other prospective studies, which could be useful in clinical practice for diagnosis influenza A (H1N1) 2009 in children. In outbreaks of a high prevalence, such as the 2009 outbreak, this test can help to prevent an overload of public health services.

Risk of cytomegalovirus transmission by cryopreserved semen: a study of 635 semen samples from 231 donors.

BACKGROUND: The hypothetical responsibility of sperm donation in cytomegalovirus (CMV) transmission to recipients and precautions to prevent this transmission are widely discussed. The aim of this French CECOS Federation study was to evaluate both the reality and the importance of the CMV risk due to donor sperm and the relevance of measures used to screen it. METHODS: We conducted a prospective multicentric study. CMV was detected by rapid and conventional cultures and by PCR in the frozen sperm of donors who met the normal criteria required of semen donors, irrespective of their CMV serological status. RESULTS: 635 samples from 231 donors (39.4% IgG(+)) were obtained and tested by culture; 551 samples from 197 donors were also tested by PCR. From those samples, 0.78% were culture(+), 1.57% culture(+) and/or PCR(+); 3.3% of seropositive donors and 0.72% of initially seronegative donors were culture(+), but in the latter seroconversion occurred during the quarantine period; of the 197 PCR-tested donors, 3.5% (6.2/1.7) were PCR(+), 3.3% (5.3/1.45) culture(+) and/or PCR(+). PCR(+) samples can be culture(-) and vice versa. The most strongly positive sample corresponded to an initially seronegative donor. CONCLUSION: The best strategy to prevent potential CMV risk is to test donors for CMV IgG and IgM antibody at the outset and after a 6 month period of quarantine and to reject initially IgM seropositive donors or donors who seroconvert during the quarantine period.

Drug-induced hypersensitivity syndrome associated with Epstein-Barr virus infection.

Association of drug-induced hypersensitivity syndrome with viral infection is debated. Human herpesvirus 6 (HHV-6) reactivation has been the most frequently reported infection associated with this syndrome. However, a case of cytomegalovirus (CMV) infection was recently described associated with anticonvulsant-induced hypersensitivity syndrome. We report a case of severe allopurinol-induced hypersensitivity syndrome with pancreatitis associated with Epstein-Barr virus (EBV) infection. Active EBV infection was demonstrated in two consecutive serum samples by the presence of anti-EBV early antigen (EA) IgM antibodies and an increase in anti-EBV EA IgG antibodies, whereas no anti-EBV nuclear antigen IgG antibodies were detected. EBV DNA was detected by polymerase chain reaction (PCR) in peripheral blood mononuclear cells. Reactivation of HHV-6 was suggested only by the presence of anti-HHV-6 IgM antibodies, but HHV-6 DNA was not detected by PCR in the serum. Other viral investigations showed previous infection (CMV, rubella, measles, parvovirus B19), immunization after vaccination (hepatitis B virus), or absence of previous infection (hepatitis C virus, human immunodeficiency virus). We suggest that EBV infection may participate in some cases, as do the other herpesviruses HHV-6 or CMV, in the development of drug-induced hypersensitivity syndrome.

Salivary cytomegalovirus (CMV) shedding, glycoprotein B genotype distribution, and CMV disease in human immunodeficiency virus-seropositive patients.

To assess the frequency of shedding of cytomegalovirus (CMV) in saliva, the distribution of CMV glycoprotein B (gB) genotypes, and the occurrence of CMV diseases, we screened 98 human immunodeficiency virus (HIV)-seropositive patients without CMV disease. CMV was detected by culture more frequently in saliva (45 [46%] of 98 patients) than in blood (7 [7.5%] of 93) and was associated with CD4 cell counts <100 cells/mm3 (P=.013). CMV in the saliva of 37 patients was successfully genotyped. Three patients (8%) were infected by a gB1 strain, 26 (70%) by a gB2 strain, 2 (5.5%) by a gB3 strain, 1 (3%) by a gB4 strain, and 5 (13.5%) by mixed gB strains. Thirteen patients developed CMV disease after a mean period of 143+/-112 days; at inclusion, 9 (69%) had salivary CMV shedding and 2 had CMV viremia. CMV salivary shedding (P=.043), low CD4+ cell count (P=.041), and CMV viremia (P=.011) were associated with occurrence of CMV disease.

Early diagnosis of adenovirus infection and treatment with cidofovir after bone marrow transplantation in children.

Adenovirus infection remains an important cause of mortality after bone marrow transplantation (BMT). Currently no efficient antiviral treatment is known. Thus, testing new modalities of early diagnosis and treatment is a crucial objective. Adenovirus infection is defined by the combination of symptoms and the isolation of virus from the source of clinical symptoms. The involvement of two or more organs and the presence of virus in blood cultures define disseminated disease. Seven children with a median age of 7 years received bone marrow transplantation for leukemia. All received an unrelated graft without T cell depletion. Adenovirus was sought in blood, urine and biopsy specimens using PCR and culture. Analysis of biopsy specimens included systematic immunohistochemistry. Cidofovir treatment was initiated as soon as biopsy revealed the histopathological signs of adenovirus. Cidofovir was given at 5 mg/kg once weekly for 3 weeks then every 2 weeks. Six patients had diarrhoea and one patient had cystitis. Adenovirus infection and disseminated disease were diagnosed in four cases and three cases, respectively. In six cases, serotype A31 was isolated from gastrointestinal biopsy and in two cases serotypes B2 and C6 were detected in blood and urine. Cidofovir treatment was associated with clinical improvement of diarrhoea, cystitis and fever in five patients, in whom the virus became undetectable in cultures and PCR analyses despite the persistence of immunodeficiency. The median follow-up was 360 days after BMT (240-570). One child died of invasive aspergillosis and another of disseminated adenovirus after interruption of cidofovir therapy. Further studies in immunocompromised patients will be needed to extend these promising results concerning the role of cidofovir in adenovirus infection.

Plasma cytomegalovirus DNA, pp65 antigenaemia and a low CD4 cell count remain risk factors for cytomegalovirus disease in patients receiving highly active antiretroviral therapy.

OBJECTIVE: To study the natural history and the current risk factors for cytomegalovirus (CMV) disease in the context of highly active antiretroviral therapy (HAART). SETTING: Prospective multicentre cohort in 15 university hospitals in France. METHODS: A group of 198 patients with CD4 cell count < 100 x 10(6) cells/l (or < 200 x 10(6) cells/l under HAART for at least 2 months), no previous CMV disease and CMV-positive serology were followed every 4 months clinically and for virological testing including HIV RNA and CMV blood markers (culture, pp65 antigenaemia, plasma CMV DNA and CMV late mRNA by the polymerase chain reaction). RESULTS: At inclusion, median CD4 was 77 x 10(6) cells/l (0-308) and 85% of the patients received protease inhibitors. The percentage of patients receiving HAART reached 99% at 12 months. After a follow-up of 23.6 months, the incidence of CMV disease was 3.2/100 patient-years [95% confidence interval (CI) 1.3-5.0]. In univariate Cox models, all the CMV markers, a CD4 cell count remaining < 75 x 10(6) cells/l and an HIV viral load > 100,000 copies/ml were predictive for CMV disease. The hazard ratios for CMV disease were 11 for blood culture; 14 and 70 for pp65 antigenaemia of > or = 1 and > or = 100 nuclei/200,000 cells, respectively; 35 for plasma CMV DNA; 6 for CMV mRNA; 29 for CD4 < 75 x 10(6) cells/l; and 12 for HIV RNA > 100,000 copies/ml. In a stepwise multivariate analysis, only three covariates were independently associated with the occurrence of a disease: plasma CMV DNA, pp65 antigenaemia > or = 100 nuclei/200,000 cells and a CD4 count < 75 x 10(6) cells/l. CONCLUSION: CMV blood markers and CD4 count < 75 x 10(6) cells/l remain risk factors for CMV disease in patients receiving HAART. Analysis of plasma CMV DNA by the polymerase chain reaction is a reproducible and standardized tool that could be used as a decision marker for initiating CMV pre-emptive therapy.

Effect of a 14-day course of foscarnet on cytomegalovirus (CMV) blood markers in a randomized study of human immunodeficiency virus-infected patients with persistent CMV viremia. Agence National de Recherche du SIDA 023 Study Group.

A randomized open-label phase 2 trial compared the virological and clinical effects on cytomegalovirus (CMV) infection of a 14-day course of intravenous foscarnet (100 mg/[kg x 12 h]) or no treatment in 42 HIV-infected patients with < 100 CD4 cells/mm3 and persistent asymptomatic CMV viremia. All CMV markers (blood culture, pp65 antigenemia, plasma and leukocyte DNA) either became negative or decreased significantly at day 14 in the foscarnet group. CMV blood culture results at day 14 were positive in 14% of those receiving foscarnet versus 60% of control patients (P = .004). However, after the end of treatment, all markers reappeared or the virus load rapidly increased. The probability of CMV disease at 6 months was 43% in both groups. Patients who had or who achieved a negative blood culture at any time had a reduced risk of CMV disease (RR = 2.64; 95% CI = 1.24-5.62; P = .02). This study suggests that sequential courses of intravenous foscarnet might not be a good strategy for preemptive therapy in this population and that in patients with a positive blood marker, treatment able to induce and maintain negative CMV blood cultures could constitute an effective intervention.

Cytomegalovirus (CMV) viremia and the CD4+ lymphocyte count as predictors of CMV disease in patients infected with human immunodeficiency virus.

We screened 192 patients infected with human immunodeficiency virus (HIV) to examine the relation between CD4+ lymphocyte counts and cytomegalovirus (CMV) viremia and the occurrence of CMV disease and subsequent duration of survival. When we stratified the viremic patients by CD4+ lymphocyte counts, the proportions were as follows: <50/mm3, 20 (25%) of 80 patients; 50-100/mm3, 2 (5.5%) of 36; 101-150/mm3, none of 14; and >150/mm3, 1 (1.5%) of 62. After a mean follow-up period of 8.5 months, 21 (11%) of 192 patients developed CMV disease. The probability of developing CMV disease at 6 months was 13% when the CD4+ lymphocyte count was <50/mm3, 3% when the CD4+ lymphocyte count was 50-100/mm3, and 0 when the CD4+ lymphocyte count was >100/mm3; this probability was 46% for viremic patients and 1% for nonviremic patients. In a multivariate analysis, CMV viremia was independently prognostic of CMV disease (relative risk, 22.03; 95% confidence interval, 6.49-78.97; P < .001), whereas a CD4+ lymphocyte count of <50/mm3 was not (P = .26). These results support the value of CMV viremia for predicting which HIV-infected patients are at risk of developing CMV disease and should therefore receive primary prophylaxis.

Comparative study of single and nested PCR for the detection of proviral HIV2 DNA.

We have tested seven pairs of primers for the detection of HIV2 DNA by single PCR in positive cultures from 21 infected patients. Four of these primer pairs were then used in a comparative study of single and nested PCR for the detection of HIV2 in fresh lymphocytes from 33 patients infected by the virus. HIV2 DNA was detected in 17 of the 33 patients (51.5%) by single PCR and 29/33 (88%) by nested PCR. All the patients negative in both nested and single PCR were asymptomatic and had CD4+ lymphocyte counts of at least 500 x 10(6)/l. This lack of PCR sensitivity for the detection of proviral HIV2 DNA in fresh lymphocytes cannot be totally attributed to genetic variability and may be related to a low viral load in asymptomatic HIV2-infected patients.