key: cord-0071528-sn5nzy2r authors: Zhao, Handan; Zhou, Minghan; Zheng, Qing; Lang, Guanjing; Xu, Lijun title: Immune status affects the clinical features and outcomes of adult patients with respiratory adenovirus infection date: 2021-10-21 journal: Epidemiol Infect DOI: 10.1017/s0950268821002272 sha: 868137bfa020406b2de8ef8868b3b4104da4feb7 doc_id: 71528 cord_uid: sn5nzy2r The differences in the clinical features and outcomes of respiratory adenovirus infection (RAI) between immunocompetent and immunocompromised adult patients remain unclear. Thirty-nine adult RAI patients, including 28 (71.8%) immunocompetent patients and 11 (28.2%) immunocompromised patients were enrolled in this retrospective study. Demographic characteristics, symptoms, laboratory tests, radiographic findings, therapies and clinical outcomes were compared between the two groups. We found fever (94.9%), cough (66.7%) and sputum production (56.4%) were the most frequent symptoms. Compared with immunocompetent RAI patients, the immunocompromised RAI patients were more likely to experience anaemia (g/l; 90.8 ± 24.0 vs 134.3 ± 14.6, P < 0.001), thrombocytopaenia ( × 10(9)/l; 116.9 ± 92.7 vs 178.4 ± 74.6, P = 0.037), hypoalbuminaemia (g/l; 29.6 ± 5.5 vs 36.9 ± 5.2, P < 0.001), hyponatraemia (mmol/l; 134.8 ± 5.6 vs 138.5 ± 3.9, P = 0.026) and low levels of cholinesterase (U/l; 2650.5 ± 1467.4 vs 5892.8 ± 1875.1, P < 0.001). Chest computed tomography (CT) scans indicated that lung infiltrate was the most common finding (64.1%). Immunocompromised patients had a higher likelihood of bilateral lung involvement (72.7%) and lower lobe involvement (81.8%) of both lungs. The hospitalized mortality rate was 27.3% in immunocompromised RAI patients, but no death occurred among immunocompetent RAI patients (P = 0.018). Our data suggested immunocompromised RAI patients had worse laboratory test results, more bilateral lung and lower lobe involvement and higher in-hospital mortality compared with immunocompetent RAI patients. Adenovirus is a double-stranded DNA virus that most often involves the respiratory tract, pharynx, conjunctiva and gastrointestinal tract [1] . Owing to a lack of humoral immunity, children <4 years old present with more than 80% of adenovirus infection cases in clinical practice [2] . Alternatively, severe adenovirus pneumonia and disseminated adenovirus infection can occur among immunocompromised adult patients [2, 3] . Occasionally, it is transmissible among healthy people living in close and crowded settings, such as college students and military recruits [2] . To date, the differences in the clinical features of RAI between immunocompromised and immunocompetent patients are still controversial. A recent study based on a small population indicated that there was no difference in clinical manifestations or the rate of severe infection between immunocompetent and immunocompromised patients [4] . However, some data demonstrated that RAI was a frequent cause of high morbidity and mortality among immunocompromised patients, with reported fatality rates reaching up to 55% [1, 5, 6] . Considering the rare and divergent data of RAI, we conducted this retrospective study to outline the clinical features and compare the outcomes of RAI between patients with immunocompetent and immunocompromised status. Between January 2010 and December 2020, 136 RAI patients were admitted to the First Affiliated Hospital, College of Medicine of Zhejiang University, Hangzhou, China. Among those, 94 patients aged less than 18 years old and three patients without diagnostic information were excluded. Finally, 39 adult patients aged 18-89 years old were included in the present study. Their information (age, sex, clinical manifestations, days of hospitalisation, underlying diseases, significant symptoms, blood test results, imaging examination results, treatments and clinical outcomes) was recorded in the electronic medical record system (EMRS). Patients were followed from the first day of admission to the day of discharge. The diagnosis of RAI was confirmed based on the following criteria [2, 3, [6] [7] [8] : (1) positive symptoms of adenovirus infection; (2) a positive polymerase chain reaction (PCR) for adenovirus in respiratory samples [nasopharynx, throat swabs or bronchoalveolar lavage fluid (BALF)] or a more than four-fold increase in serum antibody titre in the convalescence period compared to that in the acute period; (3) chest radiological examination showing lesions of viral pneumonia in the lung; (4) no improvement in clinical symptoms or laboratory results after antibacterial treatment. The severity of RAI was evaluated with the CURB-65 score, which was recommended by the British Thoracic Society. The evaluation form assigns points based on five clinical indicators ① confusion, ② urea>7 mmol/l, ③ respiratory rate≥ 30/min, ④ blood pressure (systolic (<90 mmHg) or diastolic (<60 mmHg)) and ⑤ age≥ 65 years. One point is given when in line with each indicator (range 0-5 points). A total point score≥ 3.0 was defined as severe pneumonia [9] . Immunocompromised patients represented with those: neutropenia, active solid organ or haematological malignancy, solid organ or haematopoietic stem cell transplant, uncontrolled diabetes, liver cirrhosis, significant immune deficiency (such as hypogammaglobulinaemia), human immunodeficiency virus (HIV) infection with CD4 counts<200 cells/μl or on-going treatment with chemotherapy, immune suppressive therapy (such as methotrexate, tacrolimus) or long-term (>3 months) or high-dose corticosteroids (>0.5 mg/kg/day) for more than 5 days [4, 10] . Means ± standard deviation was used to describe continuous normally distributed variables, while medians (interquartile ranges, IQRs) were applied to describe continuous nonnormally distributed variables. Differences in categorical variables between the two groups were compared by χ 2 analysis or Fisher's exact test, whereas quantitative variables were compared using Student's t-test or a nonparametric test, depending on whether they had a normal distribution. P < 0.05 (two-tailed) was defined as statistically significant. All of the data were analysed with SPSS version 22.0 (IBM, Armonk, NY, USA). This study protocol was conducted in accordance with the 1975 Declaration of Helsinki and was approved by the Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University (Hangzhou, China) (No. 2021-249). All data analysed were anonymous. No significant difference was observed in sex or age between the two groups (P = 1.000, P = 0.295, respectively). The hospitalization stay was 14.0 (10.0-22.0) days in the immunocompromised group and 7.0 (5.0-9.0) days in the immunocompetent group (P = 0.049). Additionally, there were 36.4% (4/11) immunocompromised patients and 28.6% (8/28) immunocompetent patients with smoking habits of more than 3 years (P = 0.709). (Table 1) . Fever (94.9%), cough (66.7%) and sputum production (56.4%) were the most frequent symptoms in our study. The incidence of fever was 81.8% (9/11) in immunocompromised patients and 100% (28/28) in immunocompetent patients (P = 0.074). Other atypical manifestations included sore throat (30.8%), diarrhoea (28.2%), dyspnoea (25.6%), myalgia (20.5%), etc. All of these symptoms had no statistical significance between the two RAI groups (Table 1) . We found that the haemoglobin concentration of 134.3 ± 14.6 g/l in immunocompetent patients was significantly higher than 90.8 ± 24.0 g/l in immunocompromised patients (P < 0.001). The platelet count in immunocompetent patients ((178.4 ± 74.6) × 10 9 /l) was also slightly higher than that in immunocompromised patients ((116.9 ± 92.7) × 10 9 /l, P = 0.037). Moreover, compared to total protein levels of 65.4 (58.2-69.9) g/l, albumin levels of 36.9 ± 5.2 g/l, cholinesterase levels of 5892.8 ± 1875.1 U/l and serum sodium levels of 138.5 ± 3.9 mmol/l in the immunocompetent group, the total protein levels were 58.4 (50.3-63.0) g/l, the albumin levels were 29.6 ± 5.5 g/l, the cholinesterase levels were 2650.5 ± 1467.4 U/l and the serum sodium levels were 134.8 ± 5.6 mmol/l in the immunocompromised group (P = 0.013, P < 0.001, P < 0.001 and P = 0.026, respectively). No significant differences were found in the white blood cell count, the levels of C-reactive protein, the levels of alanine aminotransferase, etc. Concomitant microorganisms including bacteria, viruses and fungi in respiratory samples were observed. There were 54.5% (6/11) immunocompromised patients and 14.3% (4/28) immunocompetent patients had other microbiological findings other than adenovirus (P = 0.017), although bacteria, virus or fungi had no statistical significance on distribution in each subgroup (P = 0.562, P = 0.187, P = 0.1125, respectively) ( Table 2) . All patients were examined by chest computed tomography (CT). In total, 64.1% (25/39) patients had lung inflammatory infiltration on radiographic images. The incidence of a right lung infiltrate was 81.8% (9/11) in the immunocompromised group, which was obviously higher than the 35.7% (10/28) in the immunocompetent group (P = 0.014). 23.1% (9/39) patients had upper lobe A left lung infiltrate was present in 81.8% (9/11) in the immunocompromised group and 35.7% (10/28) in the immunocompetent group (P = 0.014). There were 36.4% (4/11) immunocompromised patients who had left upper lobe to infiltrate compared to 14.3% (4/28) immunocompetent patients (P = 0.188). The rate of left lower lobe infiltrate was 81.8% (9/11) in the immunocompromised group, which was obviously higher than the 32.1% (9/28) in the immunocompetent group (P = 0.011). Other radiographic findings included interstitial inflammation, nodules, patchy infiltrate, fibrous proliferation and pleural infiltrate, which had no statistical significance between the two groups ( Table 2) . A total of 72.7% (8/11) immunocompromised RAI patients and 17.9% (5/28) immunocompetent RAI patients had bilateral infiltrates (P = 0.002) (Figure 1 ). Fever, cough, sputum production and increased CRP and PCT led to antibiotics use. Empirical antiviral therapy, including ribavirin, acyclovir, ganciclovir and oseltamivir, was administered to 71.8% (28/39) of the patients. Corticosteroids (33.3%, 13/39), immunoglobulin (15.4%, 6/39) and mechanical ventilation (28.2%, 11/39) were also administered to patients. No significant difference for each treatment was found between the immunocompromised group and immunocompetent group (antibiotics: P = 0.368; antiviral therapy: P = 0.187; corticosteroids: P = 0.458; immunoglobulin: P = 0.553; mechanical ventilation: P = 0.187) ( Table 2) . There were 17.9% (7/39) patients with severe pneumonia (CURB-65 scores ≥3), including 27.3% (3/11) immunocompromised RAI patients and 14.3% (4/28) immunocompetent RAI patients (P = 0.379). The overall mortality rate was 7.7% (3/39). Strikingly, the hospitalized mortality rate was 27.3% (3/11) among the immunocompromised RAI patients vs. zero among the immunocompetent RAI patients (P = 0.018) ( Table 2 ). The different manifestations of adenovirus infection between immunocompetent patients and immunocompromised patients are rarely discussed. Our current research suggests the following. (1) There was no statistical significance in clinical symptoms between the two groups. (2) Compared to immunocompetent patients, immunocompromised patients had a higher incidence of anaemia, thrombocytopaenia, hypoalbuminaemia, hyponatraemia, low levels of cholinesterase and high incidence of concomitant microorganisms in respiratory samples. (3) Immunocompromised patients had more involvement of the bilateral lungs and the lower lobes of both lungs. (4) Immunocompromised patients had higher CURB-65 scores and higher mortality rates than immunocompetent patients. Immunocompromised RAI patients had a high incidence of anaemia, thrombocytopaenia, hypoalbuminaemia, hyponatraemia and low cholinesterase levels in our study. We speculated that these abnormal laboratory test results were partly related to adenovirus infection and partly related to their underlying Epidemiology and Infection diseases. For example, an adenovirus infection could result in hepatitis and pancytopenia [11] . Therefore, it is reasonable that hypoalbuminaemia, anaemia and thrombocytopaenia could present in RAI patients. Anaemia and thrombocytopaenia are also related to poor outcomes of viral pneumonia [12, 13] . Furthermore, anaemia is a prognostic indicator for liver transplantation, AIDS and cancer [14] [15] [16] . Hypoalbuminaemia is an independent predictor of mortality in both compensated and decompensated cirrhosis, AIDS, diabetes and chronic kidney disease [17] [18] [19] [20] . Previous studies indicated that serum cholinesterase is an important clinical marker of inflammation and reduced serum cholinesterase indicates severe systemic inflammation in critically ill patients [21, 22] . Decreased serum albumin and cholinesterase could be explained by poor appetite and predisposing conditions leading to reduced intake, decreased synthesis and increased usage of proteins [23] . Serum sodium concentration is recognised as a prognostic factor in liver cirrhosis, cancer and AIDS patients [24] [25] [26] . Our study showed that the serum sodium concentration was lower in the immunocompromised group than in the immunocompetent group. It was noted that inappropriate secretion of antidiuretic hormone was found in adenovirus infected patients, which was associated with hyponatraemia [27] . Co-infection was often reported both in immunocompetent and immunocompromised individuals [7, 10, 28, 29] . Concomitant infections in immunocompromised patients tend to deteriorate into severe pneumonia and even accelerate progress to death [3, 30] . The immunocompromised had a higher co-incidence of other microorganisms in respiratory samples than the immunocompetent (P = 0.017). Several studies indicated that the initial radiographic findings of RAI were similar to those of bacterial pneumonia [30] [31] [32] . A review reported that patchy, diffuse infiltrates, consolidation and occasionally pleural effusion were major radiographic findings [6] . It seems that there are no specific radiographic characteristics to distinguish an adenovirus infection from other microbe infections. Update, few researchers have focused on radiographic characteristics of RAI patients with different immune statuses. A retrospective study in paediatric patients indicated that bilateral infiltrate was observed in 63% of patients and multifocal involvement was in 68% of patients. Furthermore, the left lower and right upper lobes were prone to be involved [33] . Meanwhile, another study showed that lower lobe involvement was commonly observed in adult RAI patients [34] . Consistent with the results of previous studies, our data showed 72.7% (8/11) of immunocompromised patients presented with bilateral lung infiltrate as opposed to 17.9% (5/28) in the immunocompetent group (P = 0.011). The lower lobes of both lungs in the immunocompromised group were more vulnerable to infiltration than those in the immunocompetent group. The bilateral and multifocal involvement might be associated with predisposing diseases. We speculated that pathogens were easier to spread in lungs under impaired immune conditions. Although antiviral drugs were empirically used, whether antiviral drugs improve clinical outcomes in the context of RAI remains controversial. Most experts believed that no medicines have been proven effective to treat adenovirus infection [2, 7, 35] . However, few studies indicated that earlier initiation of treatment might be associated with favourable clinical outcomes in immunocompromised RAI patients [36, 37] . Our present study suggested that the prognosis of RAI patients was associated with immune status. A total of 27.3% (3/11) of immunocompromised patients with severe pneumonia died, whereas 14.3% (4/28) of immunocompetent patients with severe pneumonia eventually recovered during the follow-up. The clinical characteristics of RAI in immunocompromised patients can vary from mild infections to severe conditions [32] . It was noted that RAI usually followed a fatal course in people with impaired immunity [38] . Underlying diseases also make immunocompromised patients susceptible to other pathogens [3] . Therefore, clinicians should consider the possibility of adenovirus infection in severe pneumonia patients with negative cultures and/or poor response to antibiotics. There were several limitations of our study. (1) In our retrospective study, we did not examine adenovirus types in the respiratory and blood samples, nor did we explore the relationship between different virus types and the clinical outcomes. It was reported that different serotypes had different clinical manifestations and outcomes [1, 2] . We also did not carry out viral load tests in peripheral blood or respiratory samples to further determine the potential of the viral load to predict the outcomes. (2) Our study was based on small sample size, and additional studies based on a large population are necessary to verify our findings. (3) The effects of underlying diseases on clinical presentations and radiographic features were not fully evaluated. In summary, our data demonstrated that immunocompetent and immunocompromised adult RAI patients displayed obviously different clinical features and outcomes. In particular, mortality in immunocompromised RAI patients was significantly higher than that in immunocompetent patients. 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We thank the staff of this work in the First Affiliated Hospital, College of Medicine, Zhejiang University.Author contributions. LJX designed the study and revised the manuscript. HDZ performed the study and draft the manuscript. MHZ and QZ collected the data. GJL rechecked the data. All authors reviewed and approved the final manuscript.Financial support. The work was supported by Independent Research Funding of the State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University (2020ZZ19). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. Data availability statement. The data that support the findings of this study are included in our manuscript.