We assessed 242 adults and children who received solidorgan transplants in 26 transplant centres (21 from the USA, four from Canada, and one from the Netherlands). Five patients did not meet study entry criteria and were excluded from analysis (four had nosocomially acquired infection and one had received antiviral prophylaxis), leaving 237 patients in the study. The shows the date of symptom onset, with a peak during the first week of November, 2009. The median time of symptom onset after transplant was 3.6 years (range 14 days–21.9 years). shows demographic data including type of transplant and immunosuppression. The most common transplant types were kidney and liver. Immunosuppressive treatment varied but included a calcineurin inhibitor (tacrolimus or ciclosporin) in most patients.
Date of symptom onset during pandemic
Demographics of recipients of solid-organ transplants with influenza A
The most common presenting symptoms were cough in 199 (91%) of 218 patients, then fever in 193 (85%) of 226, myalgias in 91 (51%) of 178, rhinorrhoea in 82 (43%) of 193, sore throat in 80 (43%) of 185, and headache in 59 (32%) of 186. Children were not always able to report certain symptoms. In a comparison of presenting symptoms in adult versus paediatric transplant recipients, children were substantially more likely to present with fever, rhinorrhoea, sore throat, and headache than were adult patients (). 62 (31%) of 201 patients had ill household contacts.
Clinical presentation and complications of influenza A in adult and paediatric recipients of solid-organ transplants
Imaging (chest radiograph or CT) data were available for 230 (97%) of 237 patients. Imaging was normal or unchanged in 157 (68%) patients. The remaining 73 (32%) patients had imaging findings consistent with pneumonia. The types of imaging abnormalities varied but were predominantly reported as either air space consolidation or interstitial infiltrate. Bacterial pathogens were identified from sputum or bronchoalveolar lavage fluid in 13 (6%) of 237 patients and included five patients with Staphylococcus aureus, five with Pseudomonas aeruginosa, and three with other organisms. Two patients also had fungal infections. Respiratory virus co-infections were rare and included respiratory syncytial virus (two patients) and rhinovirus (two patients). Concomitant cytomegalovirus viraemia was detected in eight (3%) of 237 patients. Other complications included four cases of otitis media, two of sinusitis, and one of encephalitis. 116 (61%) of 190 patients had lymphopenia (lymphocyte count <1000 cells per μL) at diagnosis. Serum IgG concentration before onset of illness was available for 40 patients: 19 (48%) had hypogammaglobulinaemia (IgG <7 g/L). Before symptom onset, 55 (40%) of 139 patients had received the 2009–10 seasonal influenza vaccination and 20 (11%) of 177 patients had been immunised with pandemic H1N1 vaccine. Vaccination status in the remaining patients was unknown.
To be included in the study all patients were required to have confirmed influenza A. Influenza A was subtyped as pandemic H1N1 in 162 (68%) of 237 patients. The primary method of microbiological sampling was nasopharyngeal swab in 191 (89%) of 214 patients. Influenza PCR was the main method of diagnosis in 142 (70%) of 204 patients. Other methods of diagnosis used were culture in 25 of (12%) 204 patients, direct fluorescent antibody in 29 (14%), and rapid antigen in eight (4%).
223 (94%) of 237 patients received antiviral treatment—221 (99%) were given oseltamivir. One patient was given inhaled zanamivir alone and six were given zanamivir with oseltamivir. One patient received intravenous peramivir. The 14 patients who did not receive antiviral therapy had mild illness and symptoms resolved before diagnosis. The time from symptom onset to the start of antiviral treatment was within 48 h of symptom onset in 90 (42%) of 215 patients, between 48 h and 96 h in 63 (29%), and greater than 96 h in 62 (29%). 97 (76%) of 127 adult patients received oseltamivir at the equivalent of 75 mg twice daily adjusted for renal function. 25 (20%) adult patients received the equivalent of 150 mg twice daily adjusted for renal function. 49 (96%) of 51 children received standard oseltamivir dosing according to weight. Median duration of treatment was 5 days (range 1–60). Adjunctive therapy included a reduction in immunosuppression in 52 (22%) of 232 patients. 20 (56%) of 36 patients admitted to ICU had immunosuppression reduced compared with 32 (16.3%) of 196 not admitted to ICU (p<0.001).
167 (70%) of 237 patients were admitted to hospital at a median of 2 days after symptom onset (range 1–17). The incidence of admission to the ICU was 16% (37 of 237) at a median of 5 days after symptom onset (range 1–37). Of these patients, 21 needed mechanical ventilation for a median duration of 12 days (range 2–42). Two adults and one child received extracorporeal membrane oxygenation. shows a univariate analysis of factors associated with admission to the ICU. Early antiviral treatment was associated with a lower likelihood of ICU admission (ICU admission in seven [8%] of 90 patients treated within 48 h vs 28 [22%] of 125 patients treated after 48 h; p=0.007). Early treatment with antiviral drugs was also associated with a lower incidence of admission to hospital (p=0.049; data not shown) and need for mechanical ventilation (p=0.019; data not shown).
Univariate analysis of factors associated with admission to the intensive care unit (ICU)
The multivariate analysis model for ICU admission consisted of early versus late antiviral treatment, use of antilymphocyte globulin, diabetes, and children versus adults. This model included 214 of 237 patients because 14 patients were not treated with antiviral drugs and nine patients had missing data. In this model, delayed antiviral treatment was independently associated with increased risk of admission to ICU (odds ratio [OR] 3.03, 95% CI 1.24–7.39, p=0.015). The presence of diabetes was also associated with an increased risk of ICU admission (OR 2.18, 95% CI 1.03–4.64, p=0.043).
Ten (4%) of 237 patients died at a median of 15 days after symptom onset (range 4–88). Eight (6%) of 125 patients in the group that received delayed antiviral treatment died compared with one (1%) of 90 in the group that received antiviral drugs early (p=0.059 by Kaplan-Meier analysis and log-rank statistic). The single death in this group was due to an unrelated procedural complication after the patient had recovered from influenza. Other factors associated with adverse outcome included diabetes mellitus (again associated with ICU admission and mechanical ventilation). Except for the recent use of antilymphocyte globulin, no other specific immunosuppressive drug or regimen was associated with poor outcomes.
The specific type of transplant did not seem to affect the outcomes. The 33 recipients of lung transplants, generally thought to be prone to more severe influenza, had rates of complications similar to those in receipt of other transplant types. In patients for whom information was available, seasonal influenza vaccination for 2008–09 did not have any protective effect in terms of adverse outcome: ten (14%) of 72 vaccinated patients and four (13%) of 31 unvaccinated patients were admitted to ICUs (p=1.000).
60 (40%) of 149 adults had pneumonia compared with 13 (16.0%) of 81 children (p<0.001). No other risk factor for pneumonia was identified. 47 (61.0%) of 77 children and 43 (31.2%) of 138 adults (p<0.001) received early antiviral treatment. No deaths were reported among the children.