Distribution of detected virus
One hundred and eleven samples from immunosuppressed inpatients tested positive for influenza virus using colloidal gold method were verified and classified using RT-PCR. Influenza A viruses were detected in 80 samples and the remaining 31 samples were influenza B viruses positive.
Clinical Characteristics Of Study Patients
From the Table 1, we could see that the most common immunosuppression type was malignancies with chemotherapy 87.4% (97/111), then hematopoietic stem cell transplantation 23.4% (26/111), autoimmune disorders with immunosuppressive therapy 9.0% (10/111), and solid-organ transplantation only accounted for 0.9% (1/111). Malignancies almost included all types of tumors, such as lung cancer, bone tumor, hepatoma, cholangiocarcinoma, gastrointestinal tumor, urologic tumor, gynecologic tumor, leukemia, lymphoma, other hematologic tumors, breast cancer, thyroid cancer, neuroendocrine neoplasm and retinoblastoma. Among these patients with malignancies, one patient had both breast cancer and leukemia, and two had both gynecologic tumor and leukemia. The most common transplant type was hematopoietic stem cell transplantation, one case solid-organ transplantation was kidney transplantation. The median time of symptom onset after transplant was 9 months (range 1–73 months). 66.7% (18/27) of transplant patients had rejection in preceding 3 months. Application of corticosteroids in preceding 3 months represented the proportion with 27.0% (30/111). Seasonal influenza vaccination in preceding 12 months only took up 2.7% (3/111), and these three patients had no complications and co-infections, and fever disappeared within 48 hours after antiviral treatment.
Table 1
Demographics of immunosuppressed patients with influenza infections
|
Findings (n = 111)
|
Age, median years (range)
|
51(1–92)
|
Male sex (%)
|
55(49.5)
|
Type of immunosuppression
|
|
Malignancies and chemotherapy (%)
|
97(87.4)
|
Hematopoietic stem cell transplantation (%)
|
26(23.4)
|
Solid-organ transplantation (%)
|
1(0.9)
|
Autoimmune disorders and immunosuppressive therapy (%)
|
10(9.0)
|
Comorbidity
|
|
Diabetes (%)
|
13(11.7)
|
Coronary heart disease (%)
|
4(3.6)
|
Cardiac insufficiency (%)
|
1(0.9)
|
Cerebrovascular disease (%)
|
6(5.4)
|
Chronic nephropathy (%)
|
12(10.8)
|
Chronic hepatopathy (%)
|
3(2.7)
|
Chronic lung disease (%)
|
5(4.5)
|
Smoking (%)
|
21(18.9)
|
Rejection in preceding 3 months (%)
|
18/27(66.7)
|
Interleukin-2 receptor antagonists in preceding 6 months (%)
|
9(8.1)
|
Monoclonal antibody in preceding 6 months (%)
|
3(2.7)
|
Application of corticosteroids in preceding 3 months (%)
|
30(27.0)
|
Seasonal influenza vaccination in preceding 12 months (%)
|
3(2.7)
|
Neuraminidase inhibitors application before admission (%)
|
10(9.0)
|
The most common presenting symptom was fever in 92.8% (103/111) patients, then cough 50.6% (44/87), muscular soreness 32.4% (22/68), rhinorrhea 27.4% (20/73), headache 22.5% (16/71), sore throat 22.2% (16/72), dyspnea 17.1% (13/76), gastrointestinal symptoms 15.4% (12/78), altered mental status 6.3% (6/95). (Table 2)
Table 2
Clinical presentation and complications of immunosuppressed patients with influenza infections
|
Findings
|
Fever (%)
|
103/111(92.8)
|
Sore throat (%)
|
16/72(22.2)
|
Rhinorrhea (%)
|
20/73(27.4)
|
Cough (%)
|
44/87(50.6)
|
Headache (%)
|
16/71(22.5)
|
Muscular soreness (%)
|
22/68(32.4)
|
Dyspnea (%)
|
13/76(17.1)
|
Gastrointestinal symptoms (%)
|
12/78(15.4)
|
Altered mental status (%)
|
6/95(6.3)
|
Symptom onset, hours (range)
|
24(2-456)
|
Co-infection with other infections (%)
|
21/111(18.9)
|
Complications
|
45/111(40.5)
|
Pneumonia on chest radiograph or CT scan (%)
|
42/98(42.9)
|
Acute Respiratory Distress Syndrome (%)
|
10/111(9.0)
|
Shock (%)
|
7/111(6.3)
|
Acute Kidney Injury (%)
|
4/111(3.6)
|
Viral encephalitis (%)
|
1/111(0.9)
|
Antiviral treatment (%)
|
104/111(93.7)
|
Antiviral treatment within 48 hours (%)
|
93/111(83.8)
|
No antiviral treatment within 48 hours (%)
|
18/111(16.2)
|
Oseltamivir (%)
|
79/104(76.0)
|
Peramivir (%)
|
9/104(8.6)
|
Combination of Oseltamivir and Peramivir (%)
|
16/104(15.4)
|
Standard dose of neuraminidase inhibitors (%)
|
89.4% (93/104)
|
Double dose of neuraminidase inhibitors (%)
|
11/104(10.6)
|
Admission to the intensive care unit (%)
|
16/111 (14.4)
|
Mechanical ventilation (%)
|
9/111(8.1)
|
Virus detection turned negative, days (range)*
|
3(1–11)
|
Hospital stay, days (range)
|
15(1-130)
|
Death (%)
|
11/111(9.9)
|
*Data is available only for 41 patients
|
|
From the Table 2, we also could see that the symptom onset was 24 hours (range 2-456 hours). 40.5% (45/111) patients were presence of complications. Imaging (chest radiograph or CT) data were available for 98 of 111 patients, and 42.9% (42/98) patients had imaging findings consistent with pneumonia. As to other complications, acute respiratory distress syndrome accounted for 9.0% (10/111), shock for 6.3% (7/111), acute kidney injury for 3.6% (4/111), and viral encephalitis for 0.9% (1/111).
As shown in Table 3, blood routine was characterized by lymphopenia in immunosuppressed populations with influenza infections. Erythrocyte sedimentation rate and C-reactive protein could be a little higher than normal. Albumin was usually lower than normal.
Table 3
Laboratory test results of immunosuppressed patients with influenza infections
|
Findings
|
WBC* counts (×109/L)
|
5.0 (0.0-64.7)
|
Neutrophil (%)
|
71.2 (0.0-96.4)
|
Neutrophil (×109/L)
|
3.6 (0.0-63.7)
|
Lymphocyte (%)
|
15.6 (1.4–97.4)
|
Lymphocyte (×109/L)
|
0.7 (0.0-58.1)
|
Platelets (×109/L)
|
118.0 (8.0-429.0)
|
Alanine aminotransferase (U/L)
|
21.0 (2.0-279.0)
|
Aspartate aminotransferase (U/L)
|
22.0 (6.0-198.0)
|
Albumin (g/L)
|
33.7 (20.1–48.7)
|
Lactate dehydrogenase (U/L)
|
190.0 (77.0-5536.0)
|
Creatine kinase (U/L)
|
29.0 (4.0-725.0)
|
Blood creatinine (µmol/L)
|
59.0 (22.0-189.0)
|
FiO2 (mmHg)
|
360.9 (97.5-512.6)
|
Lactic acid
|
1.2 (0.4–2.6)
|
Erythrocyte sedimentation rate (mm/h)
|
31.5 (9.0-123.0)
|
C-reactive protein (mg/L)
|
27.7 (0.5-416.9)
|
*WBC: white blood cell
|
|
Co-infections were found in 18.9% (21/111) patients, and pathogens distribution were shown in Table 4. Bacterial pathogens were identified from blood, urine, qualified sputum, or ascites in 12 (10.8%) of 111 patients, which included Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecium and Streptococcus. Two patients had fungal infections (both were Aspergillus spp.), the hospital stays of which were 90 and 51 days respectively (the latter died). Cytomegalovirus and Epstein-Barr virus viremia were detected in 8 (7.2%) and 4 (3.6%) of 111 patients, while one Herpes simplex virus and one Parainfluenza virus and two polyomaviruses (JC virus and BK polyomavirus) were detected.
Table 4
Pathogens distribution of co-infection with other infections
Patient No.
|
Bacteria (Sample type)
|
Fungi (Sample type)
|
Viruses (Blood nucleic acid)
|
7
|
Enterococcus faecium (Blood)
|
|
|
12
|
|
Aspergillus spp.(BAL + GM + chest CT)
|
Cytomegalovirus
|
14
|
Stenotrophomonas maltophilia (Qualified sputum)
|
|
|
20
|
Escherichia coli and Enterococcus faecium (Ascites)
|
|
|
23
|
|
Aspergillus spp.(BAL + GM + chest CT)
|
Parainfluenza virus and Cytomegalovirus
|
26
|
Streptococcus (Qualified sputum)
|
|
|
35
|
Escherichia coli, Klebsiella pneumoniae and Enterococcus faecium (Ascites)
|
|
|
43, 68
|
Escherichia coli (Blood)
|
|
|
61, 111
|
|
|
Cytomegalovirus
|
62, 75
|
|
|
Cytomegalovirus and Epstein-Barr virus
|
63
|
Klebsiella pneumoniae and Pseudomonas aeruginosa (Blood)
|
|
Epstein-Barr virus
|
65
|
|
|
Herpes simplex virus
|
74
|
Klebsiella pneumoniae (Blood)
|
|
Cytomegalovirus
|
77
|
|
|
Epstein-Barr virus
|
85
|
|
|
JC virus
|
99
|
Stenotrophomonas maltophilia and Enterococcus faecium (Ascites)
|
|
|
103
|
Escherichia coli (Blood and urine)
|
|
|
109
|
MRSA (Blood)
|
|
Cytomegalovirus and BK polyomavirus
|
BAL: bronchoalveolar lavage fluid
|
GM: galactomannan
|
MRSA: Methicillin-resistant Staphylococcus aureus
|
The median day of hospital stay was 15 days (range 1-130 days), and it significantly associated with organ transplantation, rejection in preceding 3 months, application of corticosteroids in preceding 3 months, complications, and co-infection with other infections (Fig. 1).
Effect Of Antiviral Therapy
104 (93.7%) of 111 patients received antiviral treatment as follows, 76.0% (79/104) were given oseltamivir, 8.6% (9/104) were given intravenous peramivir, and the remaining 15.4% (16/104) were given oseltamivir and peramivir. Combination of oseltamivir and peramivir was not significantly associated with admission to the ICU and death through the χ2 test (P>0.05).
89.4% (93/104) patients received standard dosing antiviral treatment that adult patients received oseltamivir at the equivalent of 75 mg twice or peramivir 300mg once per day, and children received standard dosing according to weight, while 10.6% (11/104) patients received double dose. Double dose of neuraminidase inhibitors was also not significantly associated with admission to the ICU and death through the χ2 test (P>0.05).
Median duration of antiviral treatment was 6 days (range 1–32). Antiviral treatment began within 48 hours of symptom onset in 83.8% (93/111), and the other 16.2% (18/111) had no antiviral treatment within 48 hours. No antiviral treatment within 48 hours was significantly associated with admission to the ICU, mechanical ventilation and death through the χ2 test (P<0.05). Median day of virus detection turned negative was 3 days (range 1–11); however, our data was available only for 41 patients, because some mild illness did not recheck and some severe illness lasted positive persistently even to death.
Risk Factors For Admission To Icu
In our study 14.4% (16/111) patients were admitted to the ICU, and we performed univariate analysis of all variables in Table 1, 2, and 3 for exploring factors with P < 0.05 associated with admission to the ICU, namely presence of organ transplantation (OR 4.00), diabetes (OR 4.94), application of corticosteroids in preceding 3 months (OR 3.32), neuraminidase inhibitors application before admission (OR 4.94), dyspnea (OR 11.08), co-infection with other infections (OR 8.57), complications (OR 7.85), and no antiviral treatment within 48 hours (OR 5.94). In multivariate logistic regression model, dyspnea (OR 32.33, 95% CI 2.07-504.56, P = 0.013), co-infection with other infections (OR 60.65, 95% CI 3.09-1188.84, P = 0.007) and no antiviral treatment within 48 hours (OR 16.28, 95% CI 1.11-238.37, P = 0.042) were independently associated with increased risks of admission to ICU. (Table 5)
Table 5
Risks for admission to ICU of immunosuppressed patients with influenza infections in Logistics analysis
Variables
|
Odds Ratio
|
(95% CI)
|
P
|
Univariate analysis
|
|
|
|
|
Organ transplantation
|
4.00
|
1.33
|
12.03
|
0.014
|
Diabetes
|
4.94
|
1.37
|
17.80
|
0.015
|
Application of corticosteroids in preceding 3 months
|
3.32
|
1.12
|
9.87
|
0.031
|
Neuraminidase inhibitors application before admission
|
4.94
|
1.22
|
20.08
|
0.025
|
Dyspnea
|
11.08
|
2.80
|
43.93
|
0.001
|
Co-infection with other infections
|
8.57
|
2.69
|
27.32
|
0.000
|
Complications
|
7.85
|
2.08
|
29.62
|
0.002
|
No antiviral treatment within 48 hours
|
5.94
|
1.84
|
19.15
|
0.000
|
Multivariate logistic regression analysis
|
|
|
|
Dyspnea
|
32.33
|
2.07
|
504.56
|
0.013
|
Co-infection with other infections
|
60.65
|
3.09
|
1188.84
|
0.007
|
No antiviral treatment within 48 hours
|
16.28
|
1.11
|
238.37
|
0.042
|
Risk Factors For Death
In our study 9.9% (11/111) patients died, and we performed univariate analysis of all variables in Table 1, 2, and 3 for exploring factors with P < 0.05 associated with death, namely presence of organ transplantation (OR 7.00), application of corticosteroids in preceding 3 months (OR 3.80), neuraminidase inhibitors application before admission (OR 4.98), dyspnea (OR 26.14), altered mental status (OR 13.83), complications (OR 17.14) and no antiviral treatment within 48 hours (OR 8.64). In multivariate logistic regression model, dyspnea (OR 26.47, 95% CI 2.53-276.66, P = 0.006) and altered mental status (OR 68.15, 95% CI 2.88-1613.81, P = 0.009) were independently associated with increased risks of death. (Table 6)
Table 6
Risks for death of immunosuppressed patients with influenza infections in Logistics analysis
Variables
|
Odds Ratio
|
(95% CI)
|
P
|
Univariate analysis
|
|
|
|
|
Organ transplantation
|
7.00
|
1.87
|
26.27
|
0.004
|
Application of corticosteroids in preceding 3 months
|
3.80
|
1.07
|
13.56
|
0.040
|
Neuraminidase inhibitors application before admission
|
4.98
|
1.08
|
23.08
|
0.040
|
Dyspnea
|
26.14
|
4.40
|
155.21
|
0.000
|
Altered mental status
|
13.83
|
2.28
|
83.86
|
0.004
|
Complications
|
17.14
|
2.11
|
139.64
|
0.008
|
No antiviral treatment within 48 hours
|
8.64
|
2.26
|
33.03
|
0.011
|
Multivariate logistic regression analysis
|
|
|
|
Dyspnea
|
26.47
|
2.53
|
276.66
|
0.006
|
Altered mental status
|
68.15
|
2.88
|
1613.81
|
0.009
|