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Clinical presentation and prognosis of the 2009 H1N1 influenza A infection in HIV-1-infected patients: a Spanish multicenter study

Riera, Melchor; Payeras, Antoni; Marcos, Maria A; Viasus, Diego; Farinas, Maria C; Segura, Ferran; Torre-Cisneros, Julian; Martín-Quirós, Alejandro; Rodríguez-Baño, Jesús; Vila, Juan; Cordero, Elisa; Carratalà, Jordi

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doi: 10.1097/QAD.0b013e32833e508f
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Abstract

Introduction

In April 2009, the WHO alerted us to an outbreak of human influenza in Mexico caused by a new variant of a virus originating from swine [1], and by June 2009 it had reached the phase of pandemic alert. The first descriptions of the clinical characteristics of patients hospitalized for influenza H1N1 showed that the new virus variant had a special preference for affecting young adult patients with underlying medical conditions, some of them caused by immunosuppression [2,3]. Based on these data, world health authorities recommended systematic vaccination for groups at risk of acquiring the infection, including those with HIV-1 infection [4,5]. Regardless of these recommendations, data on clinical presentation, complications and mortality for the 2009 pandemic influenza, the H1N1 virus infection in the group of immunosuppressed patients, particularly those infected with HIV-1, is scarce. Only one anecdotal fatal case of pneumonia, associated with 2009 pandemic influenza H1N1 virus infection in a HIV-1-infected women, has been reported until now [6].

The immunologic impairment in both humoral and T-cell responses caused by HIV-1 infection predisposes patients to acquiring viral infections. Before the widespread use of HAART, a risk of severe and prolonged influenza infections in patients infected by HIV-1 was described [7–9], although hospitalization rates owing to cardiopulmonary causes decreased during the influenza seasons in the HAART era [10]. However, there is still little information about seasonal influenza virus infections in patients infected by HIV-1. Some reports show that the influenza virus continues to be the main cause of febrile respiratory illness, and this is a possible cause of community acquired pneumonia in this population, even with patients on HAART or previously vaccinated [11,12]. This pandemic influenza is the first one to occur in a world with 43 million HIV-1-infected people and offers us the opportunity to learn more about the influenza virus behavior on HIV-1 patients.

The aim of this study was to describe clinical presentation, complications and prognosis of a subgroup of HIV-1-infected adult patients who were admitted owing to the 2009 pandemic influenza H1N1 infection in 13 hospitals in Spain. A secondary objective was to compare the clinical characteristics of the pandemic influenza H1N1 infection in these patients with those of a general population.

Methods

Setting, patients and study design

This prospective study was conducted at 13 teaching hospitals belonging to Spanish Network for Research in Infectious Diseases (REIPI). All adult patients admitted to the hospital for at least 24 h, from June 12 to November 10, 2009, with confirmed influenza A (H1N1) virus infection, were prospectively recruited and followed up. A confirmed case was defined as a person with an influenza-like illness with confirmed laboratory pandemic influenza A (H1N1) virus infection by real-time PCR or viral culture. Pandemic influenza A (H1N1) virus testing was performed in each institution.

Herein, we describe and compare two groups: the first one composed of patients with influenza and confirmed HIV-1 infection, and the second composed of all the other patients admitted with influenza.

The study was approved by the Ethics Committee of the coordinating center, Hospital Universitari de Bellvitge.

Clinical assessment and follow up

Patients were seen during their hospital stay by one or more of the investigators in each participating hospital, who recorded clinical data in a standardized, computer-assistant protocol. Data were collected on demographic characteristics, comorbidities, BMI, (the weight in kilograms divided by the square of the height in meters), clinical signs and symptoms, biochemical analysis, chest radiograph findings, antiviral and antibacterial therapy, concomitant and/or secondary bacterial pneumonia or infection, time to clinical stability, and outcomes, including mortality. In the subgroup of HIV-1-infected patients, the following variables were also collected: time since the diagnosis and risk factors for HIV-1 infection, AIDS criteria (CDC 1993), last CD4 cell count and viral load before admission, antiretroviral therapy and receipt of pneumococcal or influenza seasonal vaccines.

A long-term follow-up visit took place 1 month after discharge. For time calculations, the day of admission was considered to be hospital day 0, except for time to antiviral administration in which the day of onset of the symptoms was considered day 0.

Completed protocols were sent to the coordinating center and all the data were revised by a senior investigator previous to the final validation.

Definitions

Comorbidities were assessed by the Charlson comorbidity index. Obesity was defined as a BMI at least 30. Vaccinated patients included all individuals who had received the pneumococcal vaccine in the previous 5 years or the seasonal influenza vaccine last year. Pneumonia was defined as the presence of a new infiltrate on a chest radiograph. Concomitant and/or secondary bacterial pneumonia or infection (bacterial coinfection) was considered in patients that showed positive bacterial blood or respiratory cultures or positive urinary antigen tests for Streptococcus pneumoniae and Legionella pneumophila serogroup 1. The investigation of pathogens in sputum, pleural effusion, bronchoalveolar lavage and blood was performed by standard microbiologic procedures. Also, standard serologic methods were used to determine antibodies against atypical agents. The hospital admission criteria, microbiologic studies, ICU admission criteria, and treatment decisions were not standardized and were made by the attending physician.

Complications were defined as any untoward circumstances occurring during hospitalization. Time to clinical stability was evaluated as described elsewhere [13]. The composite outcome of overall mortality or admission to an ICU was used to evaluate severe disease. Overall mortality was defined as death from any cause within 30 days of hospitalization.

Statistical analysis

The results were analyzed using a commercially available statistical software package (SPSS, version 15.0; SPSS Inc, Chicago, Illinois, USA). A descriptive statistical analysis for all study variables was performed. All proportions were calculated as percentages of the patients with available data. To detect significant differences between epidemiologic groups, we used the χ2 test or Fisher's exact test for categorical variables when appropriate and the Student's t-test or Mann–Whitney test for continuous variables. Statistical significance was established at α = 0.05. All reported P values are two-tailed.

Results

Characteristics of participants

Five hundred and eighty-five patients with confirmed influenza A (H1N1) virus infection were recruited, including 26 patients with HIV-1 infection and 559 HIV seronegative patients. The demographic and clinical characteristics of the study participants are described in Table 1. Age, sex and pregnancy status were similar in both groups. The HIV-1 group had a higher percentage of current smokers, but they had more frequently received influenza and pneumococcal vaccine. Asthma, diabetes, chronic heart or renal disease were similar in the HIV-1 and non-HIV-1 group, but the HIV-1 group had higher chronic obstructive pulmonary disease (COPD) or chronic liver disease frequency. No patient in the HIV-1 group presented BMI more than 30, and significant differences between BMI were observed: 23.4 (2) in HIV-1 vs. 27.7 (6.2) in non-HIV-1 patients.

Table 1
Table 1:
Epidemiological and clinical characteristics of patients with pandemic (H1N1) 2009.

The HIV-1-admitted patients had a well controlled long-term infection, 88.5% were on HAART and their immunological control was good, with median CD4 cell count 503 cells/μl and 84% with undetectable viral load.

Reported symptoms, physical and laboratory findings

No differences were observed in the time from symptoms to hospitalization and the reported symptoms, although the HIV-1 patients refer to shortness of breath more frequently and less frequently to rhinorrhea and headaches, but with no statistical differences (Table 2).

Table 2
Table 2:
Diagnostic findings of patients with pandemic (H1N1) 2009.

The physical findings on hospital arrival were similar for both the HIV-1 and non-HIV-1 groups.

There was no difference in the laboratory results between the groups, except for the main frequency of thrombocytopenia. Liver enzymes, C-reactive proteins and PaO2/FiO2 levels were very similar.

Fifty percent of HIV patients and 42% of non-HIV present infiltrates as radiological findings and in 11.5 vs. 7.5% secondary bacterial pneumonia was diagnosed, with no significant differences. In both groups, S. pneumoniae was the most frequently involved bacteria.

Treatment and clinical outcome

Practically all the patients in both groups received influenza antiviral therapy, with no differences in the delay from symptoms onset, even though only 36–37% started within 48 h after the symptoms had started. See Table 3.

Table 3
Table 3:
Treatment and clinical outcomes of patients with pandemic (H1N1) 2009.

Antibacterial therapy was used in 80% of the HIV-1 group and 72% in the non-HIV-1 for similar mean days; 8.7 vs. 8.4, and steroids about 30% with no differences.

There were no observed differences in clinical outcomes: days to clinical stability, need to ICU admission: 3 (11.5%) in HIV-1 patients vs. 68 (12.2%) in non-HIV-1, and needs for mechanical ventilation: 2 (7.7%) in HIV-1 patients vs. 50 (8.9%) in non-HIV-1. No patient died in the HIV-1 group as against 13 (2.3%) in the non-HIV-1 group. The final length of hospital stay was similar: 5.9 days in the HIV-1 patients vs. 6.9 in non-HIV-1.

Discussion

We report the first comparative case-series of hospitalized HIV-1 patients with 2009 influenza AH1N1 virus infection. The pandemic strain of AH1N1 virus caused from 20 April to 23 December 2009; 271 related deaths in Spain and 10 546 viral AH1N1 infections were identified in microbiological reference laboratories (including sentinel and nonsentinel systems). Some differences in the characteristics of the participant groups are remarkable.

HIV-1 patients were more likely than non-HIV-1 patients to have received pneumococcal and seasonal influenza vaccine, which should not be surprising. Both the inactivated influenza vaccine and 23-valent polysaccharide pneumococcal vaccine are recommended in HIV-1 patients whereas few patients in the non-HIV-1 group had underlying medical conditions that justify these immunizations [14]. Thus, one could hypothesize that these vaccinations had a positive effect on the reduction of expected episodes of bacterial pneumonia and the clinical course of influenza.

The proportion of HIV-1 patients who were diagnosed with COPD (19%) was higher than the proportion observed in the non-HIV-1 group and expected in a similarly aged general population. Some recent articles suggest that the HIV-1 was an independent risk factor for COPD; in this sense more than 50% of the HIV-1 patients were current smokers, the major risk factor for COPD [15]

As expected, S. pneumoniae was the most frequently involved microorganism in secondary bacterial pneumonia in both groups. The pneumococcus is largely recognized as the main cause of bacterial pneumonia in HIV-1-infected patients [16–18], and although correlation between influenza circulation and pneumococcal pneumonia, in nonpandemic periods, varies in published studies, a modest fraction of invasive pneumococcal pneumonia associated with influenza circulation has recently been described [19].

The fact that no differences in clinical outcome were observed between HIV-1-infected and seronegative patients is remarkable. In developed countries, morbidity and mortality related to the pandemic influenza H1N1 virus infections has generally been low. In one study conducted in the USA, including 272 hospitalized patients, a mortality rate of 7% was observed and 68% of those patients had underlying medical conditions, mainly neurologic disease, asthma and COPD or pregnancy. In the multivariate analysis, the only variable significantly associated with a positive outcome was the receiving of antiviral drugs within 48 h of the illness onset [3]. Our data contrast with those previously described, taking into account that, for the majority of patients the onset of an antiviral therapy was delayed for more than 48 h, and yet the morbidity and mortality were as low for the subgroup of HIV-1-infected patients as for the whole study population. Data on morbidity and mortality of HIV-1-infected patients during influenza seasons are limited, but in one study conducted before the HAART era, HIV-1-infected women aged 15–65 years showed the highest cardiopulmonary event rates [10]. Also, excess death rates owing to pneumonia or influenza were observed in persons with AIDS for three influenza seasons (from 1991 to 1994), compared with summer periods, and excess death rates were higher than in the general population, aged 65 years and older [20]. Neuzil et al.[10] in a retrospective cohort study to estimate hospitalization and mortality rates during the influenza season, which included persons with AIDS or advanced HIV-1 infection in the Tennessee Medicaid program, observed a 53% decline in hospitalization rates for cardiopulmonary causes from 1995 to 1999, but they could not detect any effect of influenza on mortality in the post-HAART period [10].

The present study has some limitations. First, the number of cases included was low, but it is representative of a big cohort of patients followed in 13 Spanish hospitals. The sample is only composed of hospitalized patients, who were attended at the emergencies departments of the participating hospitals, so the clinical characteristics of less severe and undiagnosed pandemic influenza H1N1 virus infections could not be determined. This fact seems unlikely because the majority of cases were following regular control at outpatient clinics from their respective hospitals, as is demonstrated by the high percentage of patients with a good immunologic and virologic control. So, it is probable that during a pandemic phase of influenza, they had requested assistance from their own specialists in infectious diseases in case of influenza-like symptoms. Anyway, the characteristics of less severe cases in noncontrolled individuals can neither assessed by clinical presentation nor by the prognosis of HIV-1-infected patients in other settings, for example in countries with less medical resources. Another limitation is the lack of data on HIV-1 serology in all hospitalized patients. So, we cannot exclude that some cases included in the group of patients with no HIV-1 infection were actually HIV-1-infected.

In conclusion, in HIV patients, well controlled on HAART, the new influenza virus AH1N1 had similar clinical outcomes and prognosis to non-HIV patients.

Acknowledgments

This study was supported by the Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III, Programa de Investigación sobre gripe A/H1N1 (Grant: GR09/0014), and Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III - co-financed by European Development Regional Fund ‘A way to achieve Europe’ ERDF, Spanish Network for the Research in Infectious Diseases (REIPI RD06/0008). D.V. is the recipient of a research grant from the Institut d'Investigació Biomèdica de Bellvitge (IDIBELL).

M.R. and A.P. contributed to patient recruitment, statistical analysis and manuscript edition.

M.A.M. contributed to patient recruitment and manuscript edition.

D.V. contributed to manuscript edition and statistical analysis.

M.C.F., F.S., J.T.-C., A.M.-Q., J.V., E.C. contributed to patient recruitment and manuscript revision.

J.C. contributed to novel influenza A (H1N1) REIPI coordinator, statistical analysis, manuscript revision.

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Keywords:

HIV/AIDS; HIV-1 infection; mortality; pandemic (H1N1) 2009; pneumonia

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