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  • Original research article
  • Open Access

Clinical characteristics and outcomes of patients with severe acute respiratory infections (SARI): results from the Egyptian surveillance study 2010–2014

Multidisciplinary Respiratory Medicine201914:11

https://doi.org/10.1186/s40248-019-0174-7

  • Received: 16 November 2018
  • Accepted: 5 February 2019
  • Published:

Abstract

Background

Respiratory viral and atypical bacterial infections data in Egyptian patients are sparse. This study describes the clinical features and outcomes of patients with severe acute respiratory infections (SARI) in hospitalized patients in Egypt.

Methods

SARI surveillance was implemented at Cairo University Hospital (CUH) during the period 2010–2014. All hospitalized patients meeting the WHO case definition for SARI were enrolled. Nasopharyngeal/oropharyngeal (NP/OP) swabs were collected and samples were tested using RT-PCR for influenza A, B, respiratory syncytial virus (RSV), human metapneumovirus (hMPV), parainfluenza virus (PIV 1,2,3,4), adenovirus, bocavirus, coronavirus, enterovirus, rhinovirus, and atypical bacteria. Data were analyzed to calculate positivity rates for viral pathogens and determine which pathogens related to severe outcomes or resulted in death.

Results

Overall, 1,075/3,207 (33.5%) cases had a viral etiology, with a mean age of 5.74 (±13.87) years. The highest rates were reported for RSV (485 cases, 45.2%), PIV (125, 11.6%), and adenovirus (105, 9.8%). Children had a higher viral rate (981, 91.2%) compared to 94 (8.8%) cases in adults. Patients with identified viruses had significantly lower rates for ICU admission, hospital stay, mechanical ventilation, and overall mortality than those without identified viruses. No infections were independently associated with severe outcomes.

Conclusions

Viral pathogens were encountered in one-third of hospitalized adult and pediatric Egyptian patients with SARI, while atypical bacteria had a minor role. Highest rates of viral infections were reported for RSV, PIV, and adenovirus. Viral infections had neither negative impacts on clinical features nor outcomes of patients with SARI in our locality.

Keywords

  • Clinical
  • Outcomes
  • Viral
  • SARI
  • Egypt
  • Surveillance

Background

The World Health Organization (WHO) estimates that acute respiratory infections (ARI) cause annual deaths approaching 4 million, at a rate of more than 60 deaths/100,000 populations [1]. Viruses are responsible for 30-70 % of ARI where respiratory syncytial virus (RSV), influenza virus, parainfluenza virus (PIV), human Bocavirus, human metapneumovirus (hMPV), adenovirus, rhinovirus, enterovirus and Coronaviruses account for the majority of these cases [1, 2]. The 2009 influenza pandemic had highlighted the need for more global data on severe influenza disease, so the WHO recommended conducting surveillance for hospitalized severe acute respiratory infection (SARI), as well as influenza-like illness (ILI) in outpatients [36]. SARI surveillances are now conducted in many countries around the world; however, because of limited resources, they are only conducted in limited settings in the Middle East and Egypt [79]. Furthermore, the role of individual viral or atypical bacterial infection in causing ARI is not usually documented [10, 11].

In the current study, we analyzed surveillance data from Egyptian patients with SARI, enrolled at Cairo University Hospital (CUH) from 2010 to 2014. We aimed to calculate proportions of positive samples for different viral pathogens, to determine which pathogens were related to severe outcomes, and to address the impact of SARI on the clinical outcomes of enrolled patients, in terms of morbidity and mortality.

Methods

Study population

Cairo University Hospital (CUH) is a 5100-beds tertiary referral teaching hospital. Inclusion criteria consisted of hospitalized adults (defined as age ≥ 18 years old), as well as pediatric patients (age < 18 years old), with the diagnosis of SARI, who provided a respiratory sample, from February 2010 to February 2014. Due to an annual review by dedicated investigators and updates to WHO guidelines, the case definition for SARI has evolved over the study period. Before February 2010, as a global-surveillance case definition of SARI did not exist, the definition for SARI was adapted from the WHO protocol on rapid response for persons ≥5 years old [3]. Whereas, for children <5 years old, SARI definition was adapted from the program for Integrated Management of Childhood Illness [4]. After March 2011, the global standards and tools for influenza surveillance developed by the WHO were adopted [5]. As of January 2014, the WHO surveillance case definitions for SARI was implemented [6] as follows, acute respiratory infection with history of fever or measured fever of ≥ 38 C°; and cough; with onset within the last 10 days; and requiring hospitalization [6]. An enrollment form was used to collect data from enrolled eligible patients including patient demographics, medical history, clinical signs and symptoms, comorbidities, reported influenza vaccine status, recent travel history, treatment, clinical course, and outcome. Patients with incomplete medical records were excluded.

Clinical samples and viral detection techniques

Nasopharyngeal (NP) and oropharyngeal (OP) swabs for detecting viruses and blood cultures for detecting bacteria were taken from eligible patients on admission using operating procedures described by the WHO [12]. Specimens were taken an average of 7 days after illness onset (range: 1–66 days).

Total nucleic acid (TNA) was extracted by the automated KingFisher Flex Magnetic Particle Processor (Thermo Scientific, Waltham, MA, USA) using MagMAX Total Nucleic Acid Isolation Kit (Cat No. AM 1840, Applied Biosystems, Foster, CA, USA) according to the manufacturer’s instructions. The viral target was amplified using specific primers and probes produced by the CDC (Atlanta, GA, USA) and following standard protocol for reverse transcription polymerase chain reaction detection. From 2010 to 2012, testing for RSV, adenovirus, human parainfluenza viruses (hPIV) 1, 2 and 3, influenza (A and B) and human metapneumovirus was conducted at CUH laboratory and sent for confirmation by the Naval Medical Research Unit No.3 (NAMRU-3) laboratory. From 2013 to 2014, testing was conducted at CUH laboratory. For all samples, the human RNase P gene (RP) was tested as an internal positive control to ensure proper sample collection and nucleic acid extraction. Samples were considered positive to the viral target if the amplification curve crossed the threshold line before cycle 40. All clinical samples should be positive to RP with cutoff value ≤ 37, as prescribed previously [8]. Blood samples were collected for detection of Mycoplasma pneumonia, Chlamydia pneumonia, and Legionella pneumophila, using RT-qPCR.

Ethical standards

Prior to study initiation, the study protocol was reviewed and approved by Institutional Review Board at the NAMRU-3, as well as the ethical committee of CUH, in compliance with all applicable federal U.S. regulations governing the protection of human subjects. An informed written consent was obtained from the patients (in the case of adult patients) or patients’ parent/legal guardian (in the case of pediatric patients).

Statistical analysis

Data analyses were conducted using the software SPSS (Statistical Package for the Social Science; IBM Corp, NY, USA); version 22. Data were summarized using median (range) for quantitative variables and number and percent for qualitative variables. Comparison between groups was done using the Chi-square test for qualitative variables, independent sample t-test for normally distributed quantitative variables, while the Mann-Whitney U test was used for quantitative variables that are not normally distributed. Indicators of severe disease were assessed for each pathogen of interest using Mantel-Haenszel estimates to calculate odds ratios and confidence intervals and the Mantel-Haenszel chi-squared test to assess statistical significance [13]. Logistic regression was used to examine associations between viral respiratory pathogens and severe outcomes, defined as illness requiring ventilation or intensive care unit (ICU) or resulting in death while controlling for demographic and clinical characteristics. Only variables with statistically significant univariate association with severe outcomes were included in multivariate regression analysis. All tests were two-sided, and differences with p <0.05 were considered significant.

Results

Demographic data of the study population

Out of 3,207 participants enrolled in this SARI surveillance, 1,075 (33.5%) had positive results for viral and atypical bacteria tested. They included 569/1,075 (53%) females and 506/1,075 (47%) males. The median age was one year (range 0-85 years). Children less than 18 years had a higher viral etiology (981 patients, 91.2%) compared to 94 (8.8%) ones in adults. Notably, children <5 years represented 83% of patients. The highest rates of viral infections were reported for RSV (485 patients, 45.2%), PIV (125, 11.6%), and adenovirus (105, 9.8%). Other encountered viruses included rhinovirus, hMPV, and BOCA virus (2%,7%, and 1%, respectively). Only 3 cases were positive for Mycoplasma and were co-infected with RSV, while only one case of Chlamydia was co-infected with RSV and hMPV. Neither Coronavirus nor Legionella was detected. Table 1 shows these data.
Table 1

Demographic and clinical characteristics of patients hospitalized with severe acute respiratory infection (SARI) cases in Egypt, 2010–2014

Characteristic

Viruses Not Identified (n = 2,132) N (%)

Enrolled SARI cases (n = 1,075) N (%)

P*

RSV (n = 485) N (%)

P$

Multiple Viruses (n = 174) N (%)

P$

PIV (n = 125) N (%)

P$

Adeno-Virus (n = 105) N (%)

P$

Influenza Viruses (n = 77) N (%)

P$

Demographics

Gender

 Female

810 (38)

569 (53)

0.562

257 (53)

1.000

90 (52)

0.741

65 (52)

0.449

47 (45)

0.081

48 (62)

0.054

 Male

1,322 (62)

506 (47)

 

228 (47)

 

84 (48)

 

60 (48)

 

58 (55)

 

29 (38)

 

Age in years

 Mean ± SD

16.96 ± 25.3

5.74 ± 13.8

 

3.15 ± 9.64

 

5.48 ± 12.55

 

6.48 ± 14.82

 

4.48 ± 11.12

 

19.52 ± 23.47

 

 Median

1.0

1.0

 

0.67

 

1.0

 

1.0

 

1.0

 

5.0

 

 (Range)

(0–90)

(0–85)

 

(0–85)

 

(0–77)

 

(0–74)

 

(0–57)

 

(0–76)

 

 < 18 years

1,493 (70)

981 (91)

0.000

470 (97)

0.000

162 (93)

0.143

111 (89)

0.523

97 (92)

0.330

47 (61)

0.000

 < 1 year

831

501

 

269

 

73

 

59

 

29

 

23

 

 1–5 years

567

384

 

165

 

66

 

46

 

52

 

17

 

 >  5 years

95

96

 

36

 

23

 

6

 

16

 

7

 

 >  18 years

639 (30)

94 (9)

 

15 (3)

 

12 (7)

 

14 (11)

 

8 (8)

 

30 (39)

 

Signs & symptoms at presentation

 Shortness of breath

1,555 (73)

1,033 (96)

0.000

485 (100)

NA

174 (100)

NA

125 (100)

NA

105 (100)

NA

77 (100)

NA

 Sore throat

654 (31)

273 (25)

0.001

174 (36)

0.001

35 (20)

0.087

33 (26)

0.429

18 (17)

0.024

18 (23)

0.394

 Sputum production

1,169 (55)

566 (53)

0.077

254 (52)

0.902

86 (49)

0.396

66 (53)

0.524

63 (60)

0.068

46 (60)

0.120

 Hemoptysis

62 (3)

20 (2)

0.047

5 (1)

0.110

4 (2)

0.869

3 (2)

0.426

2 (2)

0.599

3 (4)

0.175

 Body aches

153 (7)

165 (15)

0.000

60 (12)

0.005

30 (17)

0.490

26 (21)

0.060

22 (21)

0.065

10 (13)

0.391

 Tachypnea

1,732 (81)

1,000 (93)

0.000

442 (91)

0.362

154 (88)

0.292

108 (86)

0.459

98 (93)

0.084

74 (96)

0.038

 Nasal congestion

300 (14)

647 (60)

0.000

322 (66)

0.161

113 (65)

0.244

69 (55)

0.128

53 (50)

0.397

30 (39)

0.131

 Wheezing

360 (17)

881 (82)

0.000

414 (85)

0.186

141 (81)

0.342

108 (86)

0.123

82 (78)

0.455

42 (55)

0.000

 Stridor

22 (1)

7 (0.6)

0.127

3 (0.6)

1.000

0 (0)

0.606

1 (0)

0.586

1 (0)

0.514

2 (0)

0.052

 Abnormal Breath

Sounds

955 (45)

558 (52)

0.159

239 (49)

0.140

84 (48)

0.314

74 (59)

0.054

60 (57)

0..256

49 (64)

0.023

 Nausea or vomiting

209 (10)

116 (11)

0.360

54 (11)

1.000

29 (17)

0.011

12 (10)

0.349

8 (7)

0.174

5 (6)

0.401

 Convulsions

63 (3)

108 (10)

0.000

44 (9)

0.245

18 (10)

0.891

15 (12)

0.284

17 (16)

0.026

8 (10)

0.215

Comorbidities

 Chronic Resp disease

343 (16)

460 (43)

0.002

227 (47)

0.062

52 (30)

0.044

35 (28)

0.066

45 (43)

0.078

35 (45)

0.053

 Asthma

87

119

 

77

 

22

 

21

 

28

 

26

 

 COPD

42

66

 

13

 

6

 

2

 

0

 

4

 

 Bronchiectasis

101

133

 

88

 

11

 

9

 

12

 

2

 

 Othersa

113

142

 

49

 

13

 

3

 

5

 

3

 

 Cardiac disease

512 (24)

214 (20)

0.392

81 (17)

0.046

37 (21)

0.050

31 (25)

0.078

26 (25)

0.055

12 (16)

0.158

 Heart failure

299

44

 

22

 

13

 

14

 

9

 

7

 

 Congenital HD

114

147

 

48

 

15

 

11

 

15

 

2

 

 Cardiomyopathy

99

23

 

11

 

9

 

6

 

2

 

3

 

 Endocrine disease

147 (7)

124 (12)

0.000

50 (10)

0.249

19 (11)

0.897

24 (19)

0.004

13 (12)

0.420

12 (16)

0.158

 Diabetes mellitus

100

106

 

37

 

12

 

21

 

11

 

11

 

 Obesity

47

18

 

13

 

7

 

3

 

2

 

1

 

 Neuromuscular

disease

176 (8)

90 (8)

0.001

30 (6)

0.033

15 (9)

0.063

19 (15)

0.012

10 (10)

0.398

6 (8)

0.233

 Muscle dis

123

37

 

13

 

11

 

12

 

6

 

4

 

 Epilepsy

53

53

 

17

 

4

 

7

 

4

 

2

 

 Renal disease

43 (2)

11 (1)

0.951

5 (1)

0.866

0 (0)

0.322

3 (2)

0.198

0 (0)

0.314

2 (3)

0.200

 Chronic RF

34

9

 

5

   

3

   

2

 

 Nephrotic Syndrome

9

2

 

0

   

0

   

0

 

 Hepatic disease

54 (3)

9 (1)

0.002

2 (0.5)

0.001

3 (2)

0.192

2 (2)

0.277

1 (1)

0.579

1 (1)

0.496

 Ch hepatitis

9

5

 

2

 

2

 

0

 

1

 

1

 

 Liver cirrhosis

33

3

 

0

 

1

 

2

 

0

 

0

 

 Hepatic failure

12

1

 

0

 

0

 

0

 

0

 

0

 

 Hematologic disease

23 (1)

5 (0.5)

0.583

0 (0)

0.051

1 (0.5)

0.428

1 (1)

0.377

2 (2)

0.079

1 (1)

0.496

Clinical course

 Pneumonia

175 (8)

29 (3)

0.004

13 (2.6)

0.033

4 (2)

0.066

1 (1)

0.288

4 (4)

0.054

3 (4)

0.299

 Admission to ICU

606 (28)

219 (20)

0.000

82 (17)

0.022

41 (23)

0.123

20 (16)

0.007

22 (21)

0.064

36 (47)

0.045

 Mechanical ventilation

221 (10)

100 (9)

0.412

43 (9)

0.052

13 (7)

0.778

8 (6)

0.373

7 (7)

0.213

17 (22)

0.001

Complications

 Respiratory failure

45 (2)

22 (2)

0.033

9 (2)

0.552

4 (2)

0.488

2 (2)

0.607

4 (4)

0.101

1 (1)

0.349

 ARDS

3 (0.1)

15 (1.5)

0.011

8 (2)

0.063

4 (2)

0.072

0 (0)

0.237

0 (0)

0.064

0 (0)

0.078

Outcomes$

 Discharged

1,852 (87)

956 (89)

0.005

433 (89)

0.045

153 (88)

0.051

116 (93)

0.289

100 (95)

0.131

62 (81)

0.006

 Transferred

174 (8)

95 (8.8)

 

40 (8.6)

 

20 (11.5)

 

7 (6)

 

3 (3)

 

10 (13)

 

 Died

106 (5)

24 (2.2)

 

12 (2.4)

 

4 (2)

 

1 (1)

 

2 (2)

 

4 (5)

 

*P for comparison between virus-infected (SARI-positive) and non-infected (SARI-negative) individuals. P$ for SARI patients with a positive result for that pathogen compared to a reference group of tested SARI patients with a negative result for that pathogen. RSV Respiratory syncytial virus, PIV Para-influenza virus, ICU Intensive care unit, ARDS Acute respiratory distress syndrome, NA Not available a Others; immotile cilia syndrome, interstitial lung disease

Clinical characteristics of viral-infected versus no virus-detected individuals

In comparison to non-viral infected individuals, viral-infected SARI ones had significantly predominant signs and symptoms at presentation. Particularly, they had significant viral prodromal symptoms, as well as tachypnea, wheezes, and convulsions (p=0.000 each). Among individual viral pathogens, SARI patients with influenza had more significant tachypnea (p= 0.038), wheezes (p=0.000), and abnormal breath sounds (p= 0.023), than those with non-influenza viral infections. Patients whose specimens were collected within 5 days of the onset of symptoms were more likely to have a viral pathogen detected than those whose specimens were collected later (73% versus 36%, p = 0.047).

Fifty-three percent of patients had at least one underlying medical condition. These comorbidities included chronic respiratory disorders (asthma, COPD, bronchiectasis, and immotile cilia syndrome), cardiac disorders (heart failure congenital heart diseases, and cardiomyopathy), neuromuscular disorders (epilepsy, cerebral palsy, and myopathies), hematological disorders (thalassemia), endocrine disorders (diabetes mellitus, hypothyroidism, and morbid obesity), renal disorders (end-stage renal disease), and liver disorders (liver cirrhosis and hepatic failure).

Patients with comorbidities (n = 570, 53%) were significantly older compared to those with no comorbidities (median age: 54 versus 3, p <0.001). Additionally, they were significantly more likely to be symptomatic.

In terms of comorbidities, patients with and without viral detection differed significantly in the frequencies of chronic respiratory (p=0.002), endocrine (p=0.000), hepatic (p=0.002), and neuromuscular disorders (p=0.001). Among individual viral pathogens, SARI patients with para-influenza virus had significant endocrine (p= 0.004), and neuromuscular disorders (p=0.012), than those with non-para-influenza viral infections.

For influenza vaccination history; 832/1,075 (77.4%) cases did not receive the vaccine within the 12 months prior to hospital admission, while 243/1,075 (22.6%) were reported as unknown for an influenza vaccination status. Table 1 details these results.

Clinical course, complications, and outcomes in viral-infected patients

In comparison to non-viral infected individuals, viral-infected SARI ones had significantly lower rates of pneumonia (p=0.004) and admission to the ICU (p=0.000). Patients with influenza virus tended to have significantly different rates of admission to the ICU (p=0.045), and mechanical ventilation (p=0.001), in comparison to those with non-influenza infections. With regards to complications, viral-infected SARI patients had significant differences for developing respiratory failure (p=0.033), and acute respiratory distress syndrome; ARDS (p=0.011), in comparison to those without viral infections.

Overall mortality in SARI-positive patients was 24/1,075 (2.2%) and peaked at 1% in 2014. Overall, only 2(8%) were adults, while 22 (92%) were children. Among children, 18(75%) were aged <5 years. Overall, two-thirds (16/24) had comorbidities. All patients who died were admitted to the ICU and mechanically ventilated. Notably, all patients who died tested positive for a viral pathogen; twelve were positive for RSV, four for influenza virus, two for adenovirus, one for hMPV, one for PIV and four for mixed viral infections, respectively. Among those who died, there was a significant difference between those with (2.2%) and without (5%) viral detection (p = 0.005). Among individual viral pathogens, SARI patients with RSV and influenza had significant deaths (p= 0.045 and 0.006), in comparison to those with non-RSV and non-influenza viral infections. No mortality was reported for patients with atypical bacteria (Table 1).

Severe outcomes in viral-infected patients

No infections were independently associated with increased severity of SARI, as indicated by illness requiring mechanical ventilation and/or ICU and/or resulting in death. There was strong evidence that individuals with RSV and influenza were less likely to experience a severe outcome than those not infected with each of these pathogens (RSV OR 1.433, 95% CI 4.698-6.132. p=0.021, influenza OR 3.937, 95% CI 2.447-6.3340, p=0.000). Individuals with multiple infections were no more likely than those with infection with a single pathogen to experience severe outcomes (OR 0.232, 95% CI 0.155-0.619, p = 0.240).

When analyses were stratified by age, neither significant differences in severe outcomes could be encountered between viral-infected and non-infected individuals (OR 0.983, 95% CI 0.503-1.924, p=0.961 and OR 1.100, 95% CI 0.704-1.718, p=0.675) nor between individual viral infections, among children and adults. Table 2 shows these details (Data for PIV, hMPV, Boca virus, rhino-, and enterovirus are not shown in the table).
Table 2

Indicators of the severity of SARI by pathogen and age

 

SARI cases

RSV

Adenovirus

Influenza

Multiple Viruses

No (%)

OR (95%

CI)

P*

No (%)

OR (95% CI)

P$

No (%)

OR (95% CI)

P$

No (%)

OR (95% CI)

P$

No (%)

OR (95% CI)

P$

All participants

 Ventilation

100/

1,075

(9)

1.280

(0.703-

2.329

0.419

43/485

(9)

0.177

(−1.005-

0.185)

0.866

7/105

(7)

1.293

(0.682-

2.452)

0.431

17/77

(22)

3.123

(1.743-

5.598)

0.000

13/174

(7)

0.755

(0.412-

1.386)

0.365

 ICU

219/

1,075

(20)

0.972

(0.706-

1.337)

0.861

82/485

(17)

1.897

(12.591-

13.635)

0.017

22/105

(21)

1.040

(0.634-

1.707)

0.876

36/77

(47)

3.910

(2.431-

6.290)

0.000

41/174

(23)

0.225

(0.162-

0.612)

0.254

 Death

24/

1,075

(2)

0.00

(0.941-

0.966)

0.557

12/485

(2)

0.530

(−1.215-

0.625)

0.637

2/105

(2)

0.837

(0.194-

3.609)

0.811

4/77

(5)

0.986

(−0.114-

2.085)

0.079

4/174

(2)

0.036

(1.050-

1.122)

0.948

 Severe Outcome

219/

1,075

(20)

0.972

(0.706-

1.337)

0.861

82/485

(17)

1.433

(4.698-

6.132)

0.021

22/105

(21)

1.047

(0.638-

1.738)

0.857

36/77

(47)

3.937

(2.447-

6.334)

0.000

41/174

(23)

0.232

(0.155-

0.619)

0.240

Children <18 years

 Ventilation

66/

981

(7)

1.032

(0.305-

3.541)

0.952

36/485

(8)

0.894

(0.566-

1.413)

0.632

7/105

(7)

0.907

(04.05-

2.032)

0.812

5/77

(6)

1.785

(0.676-

4.713)

.0243

13/174

(7)

0.995

(0.536-

1.849)

0.988

 ICU

178/

981

(18)

0.983

(0.503-

1.924)

0.961

68/485

(14)

0.838

(0.594-

1.182)

0.314

11/105

(10)

0.691

(0359-

1.330)

0.268

10/77

(13)

2.008

(0.952-

(4.237)

0.067

32/174

(18)

1.418

(0.921-

2.185)

0.113

 Death

13/

981

(1)

0.973

(0.960-

(0.987)

0.784

12/485

(2)

1.363

(0.583-

1.385)

0.474

2/105

(2)

0.966

(0.222-

4.198)

0.963

2/77

(2)

2.640

(0.594-

11.740)

0.202

4/174

(2)

1.162

(0.338-

3.479)

0.789

 Severe Outcome

178/

981

(18)

0.983

(0.503-

1.924)

0.961

68/485

(14)

0.849

(0.602-

1.199)

0.353

11/105

(10)

0.697

(0.362-

1.342)

0279

10/77

(13)

2.024

(0.959-

4.271)

0.064

32/174

(18)

1.432

(0929-

2.206)

0.114

Adults >18 years

 Ventilation

34/94

(36)

1.357

(0.645-

2.856)

0.421

7/485

(1)

0.966

(0.114-

2.085)

0.078

0/105

(0)

2.991

(0.851-

10.514)

0.088

12/77

(16)

2.878

(1014-

8.166)

0.052

0/174

(0)

0.787

(0.669-

0.885)

0.063

 ICU

41/94

(44)

1.100

(0.704-

1.718)

0.675

14/485

(3)

1.493

(0.282-

2.452)

0.527

11/105

(10)

3.235

(0.671-

15.593)

0.143

26/77

(34)

0.929

(0.392-

2.198)

0.866

9/174

(5)

0.606

(0.203-

1.815)

0.371

 Death

11/94

(12)

0.934

(0.912-

0.965)

0.793

0/485

(0)

0.848

(0.437-

1.196)

0.691

11/105

(10)

0.859

(0.790-

0.933)

0.645

2/77

(2)

0.413

(0.324-

0.527)

0.351

0 (0)

0.826

(0.752-

0.907)

0.763

 Severe Outcome

41/94

(44)

1.100

(0.704-

1.718)

0.675

14/485

(3)

1.493

(0.282-

2.452)

0.527

0/105

(0)

3.235

(0.671-

15.593)

0.143

26/77

(34)

0.929

(0.392-

2.198)

0.866

9/174

(5)

0.606

(0.203-

1.815)

0.371

*P for comparison between virus-infected (SARI-positive) and non-infected (SARI-negative) individuals. P$ for SARI patients with a positive result for that pathogen compared to a reference group of tested SARI patients with a negative result for that pathogen. RSV Respiratory syncytial virus, PIV Para-influenza virus, ICU Intensive care unit, Severe outcome is defined as illness requiring ventilation or ICU or resulting in death

Logistic regression was used to further examine associations with severe outcomes in SARI-positive individuals with complete demographic data and clinical risk factors. By univariate analysis, individuals with positive results for rhinovirus and adults >18 years were more likely to experience a severe outcome than those not infected with rhinovirus (OR 4.975, 95% CI 2.431-17.812, p=0.024) and children <18 years (OR 10.357, 95% CI 5.895-18.197, p=0.000), respectively.

Multivariate analysis confirmed these results where individuals with positive results for rhinovirus and adults >18 years were more likely to experience a severe outcome than those not infected with rhinovirus (OR 4.807, 95% CI 2.981-16.112, p=0.025) and children <18 years (OR 11.716, 95% CI 7.225-18.998, p=0.000), respectively.

Table 3 shows these results.
Table 3

Univariate and multivariate logistic regression for predictors of severe outcomes among viral-infected SARI cases

Univariate Analysis

  

OR (95% CI)

P

RSV

Negative

ref

Positive

0.00 (−)

0.989

Adenovirus

Negative

ref

Positive

0.927 (0.533–1.612)

0.788

Rhinovirus

Negative

ref

Positive

4.975 (2.431–17.812)

0.024

Enterovirus

Negative

ref

Positive

0.00 (−)

1.000

Influenza

Negative

ref

Positive

1.150(0.608–2.176)

0.667

BOCA virus

Negative

ref

Positive

0.413 (0.051–3.371)

0.409

HMPV

Negative

ref

Positive

0.845 (0.431–1.656)

0.624

PIV

Negative

ref

Positive

0.633 (0.361–1.112)

0.112

Multiple viruses

Single virus

ref

Multiple viruses

1.515 (0.974–2.357)

0.065

Age

Adults >18 years

ref

Children <18 years

10.357 (5.895–18.197)

0.000

Gender

Male

ref

Female

0.893 (0.643–1.239)

0.497

Comorbidities

None

ref

Any

1.181 (0.840–1.661)

0.338

Multivariate analysis

  

OR (95% CI)

P value

Rhinovirus

Negative

ref

Positive

4.807 (2.981–16.112)

0.025

Age

Adults >18 years

ref

Children <18 years

11.716 (7.225–18.998)

0.000

RSV Respiratory syncytial virus, hMPV Human metapneumovirus, PIV Para-influenza virus, OR Odds ratio

Comparison between RSV-positive and other viral cases

Being the most commonly detected virus among our cohort, clinical characteristics and outcomes of RSV-positive patients were compared to those with other respiratory positive cases as well as viral-negative patients.

While patients with RSV-positive infections had significant differences with those with no respiratory viruses identified, with regards to clinical signs and symptoms, comorbidities, and outcomes (ICU admission and deaths); they had no differences with those tested positive for other viral pathogens, with regards to the same parameters. (Table 4 shows these details)
Table 4

Comparison of SARI patients with RSV to those with a non-RSV or to those with no respiratory virus identified

Characteristic

RSV-positive (n = 485) N (%)

Other Viruses Positive (n = 590) N (%)

P*

No virus Identified

(n = 2132) N (%)

P$

Gender

 Female

257 (53)

312 (53)

0.203

810 (38)

0.000

 Male

228 (47)

278 (47)

 

1,322 (62)

 

Age

 Below 18 y

470 (97)

511 (87)

0.801

1,493 (70)

0.373

 Above 18 y

15 (3)

79 (13)

 

639 (30)

 

Symptom onset ≤7 days

456 (94)

480 (81)

0.064

1,211 (57)

0.250

Cough

485 (100)

536 (91)

0.882

2,132 (100)

1.000

SOB

485 (100)

548 (93)

1.000

1,555 (73)

0.077

Fever

485 (100)

590 (100)

1.000

2,132 (100)

1.000

Sore throat

174 (36)

311 (53)

0.000

654 (31)

0.000

Sputum production

254 (52)

312 (53)

1.000

1,169 (55)

0.870

Body aches

60 (12)

105 (18)

0.063

153 (7)

0.004

Tachypnea

442 (91)

558 (95)

0.063

1,732 (81)

0.087

Nasal congestion

322 (66)

325 (55)

1.000

300 (14)

0.060

Wheezing

414 (85)

467 (79)

0.031

360 (17)

0.063

Abnormal BS

239 (49)

319 (54)

0.008

955 (45)

0.022

Nausea or vomiting

54 (11)

62 (10)

0.988

209 (10)

0.003

Convulsions

44 (10)

64 (11)

0.677

63 (3)

0.046

pneumonia

13 (3)

16 (3)

1.000

175 (8)

0.001

Chronic lung disease

227 (47)

233 (39)

0.086

343 (16)

0.001

Cardiac disease

81 (17)

133 (23)

0.063

512 (24)

0.022

Endocrine disease

50 (10)

74 (13)

0.866

147 (7)

0.002

Renal disease

5 (1)

6 (1)

1.000

43 (2)

0.246

Neuromuscular disorder

30 (6)

60 (10)

0.333

176 (8)

0.033

ICU

82 (17)

137 (23)

0.121

606 (28)

0.000

Ventilation

43 (9)

57 (10)

0.473

221 (10)

0.343

ARDS

8 (1)

7 (1)

1.000

3 (0)

0.000

Respiratory Failure

9 (2)

13 (2)

0.988

45 (2)

1.000

Death

12 (2)

12 (2)

1.000

106 (5)

0.000

*P for comparison for SARI patients with a positive result for RSV (RSV-positive SARI patients) and a reference group of tested SARI patients with a negative result for RSV (non-RSV-positive SARI patients).P$ for comparison between RSV-positive SARI patients and non-infected individuals (SARI-negative individuals); RSV Respiratory syncytial virus, SOB Shortness of breath, ICU Intensive care unit, ARDS Acute respiratory distress syndrome

Severe outcomes in RSV-positive patients

Logistic regression was used to examine associations with severe outcomes in RSV-positive patients with complete demographic data and clinical risk factors. By univariate analysis, individuals with RSV and associated comorbidities were more likely to experience severe outcomes (OR 4.703, 95% CI 0.803-9.672, p=0.001) than those with RSV and no comorbidities (Table 5).
Table 5

Logistic regression for predictors of severe outcomes for RSV-positive cases

Univariate analysis

  

OR (95% CI)

P

Gender

Male

ref

Female

1.600 (0.400–6.163)

0.086

Age

Adults >18 years

ref

Children <18 years

1.119 (0.276–4.466)

0.151

Comorbidities

None

ref

Any

4.703(0.803–9.672)

0.001

RSV Repiratory syncytial virus, OR Odds ratio

Discussion

To the best of our knowledge, this is the largest surveillance Egyptian study that addressed the epidemiological patterns of SARI due to viruses and atypical bacteria in both children and adult population and their relation to the clinical characteristics and outcomes of those patients.

The worldwide distribution of viral etiology as a cause of SARI varies between 2% and up to 78% [7, 11, 13, 14]. In this study, we found a viral etiology in 33.5 % of hospitalized patients with SARI, which is comparable to previous studies conducted in either developing or Middle Eastern countries [911, 13]. The finding that two-thirds of SARI cases had no pathogen detected suggests that poor or late specimen collection may have contributed to a lower yield of detected viruses. Interestingly, children <18 years represented the majority (91.2%) of our cohort. Notably, this contradicts findings observed by other studies [14, 15]. In their surveillance for SARI in Northern Vietnam, Nguyen et al [15] observed that 22.7% of their cohort were children <18 years, while 77.3% were adults >18 years. Again, children <5 years represented 83% of our cases. This is in accordance with those surveillance data from Southern Arizona, 82% [14], lower than those from China (94% in <72 months) [16] and higher than in Kenya,71% [11].

The highest rates of viral infections were reported for RSV (45.2%), PIV (11.6%), and adenovirus (9.8%), with a relatively low rate (7.2%) for influenza viruses. Not unexpected, RSV was the most predominant respiratory virus with a prevalence of 45%; emphasizing its role as the major cause of SARI in infants and young children worldwide [7, 8, 1317]. Notably, the proportion of SARI cases positive for RSV in children <5 years in our surveillance (90%) was markedly higher than those reported in surveillance data from Kenya, 21% [11], Southern Arizona, 31% [14], and even higher than previous studies in Egypt [18].

We observed that, SARI cases <5 years were significantly more likely than older patients to be infected with each of the pathogens examined, particularly for RSV and influenza. As the majority of enrolled patients were children (83%), this is not unexpected since these pathogens have a strong association with this age group. This is inconsistent with data that nearly 80% of children are exposed to RSV by age two, 100% to hMPV by age five and 90% to hPIV by age five [19]. Furthermore, hPIV is a significant etiology of LRTI in children [20], second only to RSV [21], and adenoviruses are the second most common viral pathogen in children under two years of age [7].

Notably, our results showed a very minor role for atypical bacteria in causing SARI in our locality. Only 3 cases were positive for Mycoplasma (co-infected with RSV), while only one case of Chlamydia was co-infected with RSV and hMPV. Clinical presentations differed significantly between those with non-viral infected individuals and viral-infected SARI ones. The later had significant viral prodromal symptoms, as well as tachypnea, wheezes, and convulsions. Furthermore, SARI patients with influenza had significant tachypnea, wheezes, and abnormal breath sounds, than those with non-influenza viral infections. The presence of these signs at presentation could help the clinician predicting the likely pathogen causing SARI [14].

Fifty-three percent of our patients had medical comorbidities, with the predominance of chronic lung diseases (43%). The impacts of medical comorbidities on patients with SARI were addressed in previous surveillance studies [9, 13, 14]. Despite that 83% of our cohort were children less than 5 years, and patients with comorbidities were significantly older compared to those with no comorbidities, patients with and without viral detection differed significantly in the frequencies of chronic respiratory, as well as endocrine, hepatic and neuromuscular disorders.

Comparing the clinical course, complications, and outcomes between viral-infected cases and non-viral detected controls showed interesting results. Patients with identified viruses had significantly lower rates for ICU admission, hospital stay, length of mechanical ventilation, and overall mortality than those without identified viruses. However, there were no differences with regards to ARDS and mechanical ventilation.

Previous studies showed conflicting results on the impacts of viral infections on clinical outcomes in patients with SARI [9, 13, 14, 19, 22, 23]. Differences in patients’ numbers, enrollment criteria, and methodologies could explain these results. Although PCR has been established as a reliable diagnostic assay with high sensitivity and specificity for respiratory viruses, particularly for RSV [24], the clinical implications of positive laboratory results are still less clear [13].

Patients with positive viral detection had better clinical outcomes than those with no viral detection, in terms of pneumonia, ICU admission, and overall mortality. Furthermore, compared to patients with no virus identified, patients with RSV-positive infection were significantly less likely to have pneumonia, to be admitted to the ICU, mechanically ventilated, and had less mortality.

Interestingly, analyses to assess associations with severe outcomes in the current study revealed that no infections were independently associated with those outcomes, even after controlling for age and associated medical comorbidities. Despite the predominance of RSV infections among SARI-positive cases (45%), there was strong evidence that individuals with RSV and influenza were less likely to experience a severe outcome than those not infected with each of these pathogens. Furthermore, individuals with multiple infections were no more likely than those with infection with a single pathogen to experience severe outcomes.

Multivariate logistic regression analysis confirmed that individuals with positive results for rhinovirus and adults >18 years were more likely to experience a severe outcome than those not infected with rhinovirus and children <18 years, respectively. However, because of the low prevalence of rhinovirus (2%) and adults (8.8%) in this study, further larger studies are needed to confirm these associations.

Being the most commonly detected virus among our cohort, there was an interest to examine the RSV-positive cases. Interestingly, while patients with RSV-positive infections had significant differences with those with no respiratory viruses identified with regards to clinical signs and symptoms, comorbidities, and outcomes; they had no differences with those tested positive for other viral pathogens with regards to the same parameters.

However, individuals with RSV and associated medical comorbidities were more likely to experience severe outcomes than those with RSV and no comorbidities, after controlling for age and other risk factors.

Again, review of the literature had shown conflicting results for clinical implications of RSV infection [9, 2328]. While the relationship between RSV infection and clinical disease has been established, as infections among asymptomatic individuals are rare [9, 2427], no relationship between viral load and disease severity was identified by others [23, 28, 29]. For non-influenza viruses, the clinical features are still unclear. Adenovirus infection levels in asymptomatic children and adults varied [27, 30], though this may be attributable to differences in sampling methodology since throat swabs may detect latent AdV DNA in tonsil tissue [27]. Studies suggest that asymptomatic infection with hMPV is rare among children [31], but results from adult populations are less conclusive, with reports of varying levels of infection among asymptomatic individuals [25, 32].

Furthermore, the clinical implications of positive laboratory results are further complicated by the presence of co-infections. Multiple viral respiratory pathogens were identified in 16.7% of our cases. Co-infection with 2 or more viral respiratory pathogens has been encountered in previous reports among pediatric populations in the Middle East [13, 18, 33, 34]. Multiple infections complicate diagnosis, as the relative clinical impact of each pathogen is unclear [13], and certain pathogens, such as adenovirus, are routinely found in the upper airways [35].

This study has many points of strength; it was the first surveillance that addresses the clinical impacts and epidemiological patterns of viral and atypical bacteria causing SARI in both children and adult Egyptian population, with enrolled large numbers of patients and over a relatively long period. Furthermore, analyses of homogenous populations, rather than different ethnic groups [14], give the results reliable and strong support. On the other hand, it has some limitations; more time may be needed for properly evaluating the role of atypical bacteria, and the flu vaccine was not used.

Conclusions

The current study showed that viral pathogens were encountered in one-third of hospitalized adult and pediatric Egyptian patients with SARI. Atypical bacteria had a minor role in SARI in our locality. Highest rates of viral infections were reported for RSV, PIV, and adenovirus. The presence of chronic respiratory, endocrine, hepatic and neuromuscular disorders negatively affects patients with identified viral infections. Viral infections had no negative impacts on clinical features, clinical course, and severe outcomes of SARI in our locality. Further studies are warranted.

Abbreviations

ARDS: 

Acute respiratory distress syndrome

ARIs: 

Acute respiratory infections

CDC: 

Center of Disease Control

CUH: 

Cairo University Hospital

HBOV: 

Human Bocavirus

hMPV: 

Human metapneumovirus

Ig: 

Immunoglobulin

ILI: 

Influenza-like illness

IQR: 

Interquartile range

NP: 

Nasopharyngeal

OP: 

Oropharyngeal

OR: 

Odds Ratio

PIV: 

Parainfluenza virus

RSV: 

Respiratory syncytial virus

RT-qPCR: 

Quantitative real-time reverse transcription polymerase chain reaction

SARI: 

Severe acute respiratory infection

VTM: 

Viral transport medium

WHO: 

World Health Organization

Declarations

Acknowledgments

The authors thank the nursing team at Cairo University Hospitals (CUH) and the technician teams of the laboratory departments of CUH and the Naval Medical Research Unit No.3 (NAMRU-3) for their contribution to this work.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors’ contributions

All authors have provided approval of the manuscript to be published. AH, SM, UA, and EI contributed to the draft of the submitted revised article, revised it critically for important content, and made substantial contributions to conception and design, as well as data acquisition, analysis, and interpretation; AH and MR contributed to the draft of the submitted article and made substantial contributions to acquisition, analysis, and interpretation of clinical data of patients admitted to the ICU. AE and MH contributed to the draft of the submitted article and made substantial contributions to acquisition, analysis, and interpretation of laboratory data.

Ethics approval and consent to participate

The study protocol was approved by the Institutional Review Board at the NAMRU-3, as well as the ethical committee of Cairo University Hospital (CUH), in compliance with all applicable federal U.S. regulations governing the protection of human subjects. Informed written consent was obtained from the patients (in the case of adult patients) or patients’ parent/legal guardian (in the case of pediatric patients).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Authors’ Affiliations

(1)
Department of Chest Diseases, Faculty of Medicine, Cairo University, Cairo, Egypt
(2)
Department of Chest Diseases and Tuberculosis, Faculty of Medicine, Assiut University, Assiut, 71516, Egypt
(3)
Department of Anesthesia and Intensive Care, Faculty of Medicine, Cairo University, Cairo, Egypt
(4)
Department of Clinical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
(5)
Department of Clinical Pathology, Faculty of Medicine, Mansura University, Mansura, Egypt

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