As of May 7, the Italian National Institute of Health reported 3752 cases of severe acute respiratory syndrome associated with coronavirus 2 (SARS-CoV-2) in Italian children <18 years of age, 140 of them requiring hospital admission.
Since the first outbreak, a global effort has been made to collect clinical and laboratory findings on patients with SARS-CoV-2 infection. The lower airway is the primary target of the infection; however, the disease spectrum in adults goes from asymptomatic subjects to sever illness including 5.0% subjects requiring intensive care unit (ICU) admission, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died.1 Data suggest that children are less likely to develop severe symptoms compared with adults.2 Also, there are growing evidence of clinical manifestations other than acute respiratory syndrome in pediatrics suggesting that coronavirus diseases 2019 (COVID-19) spectrum and pathogenesis in children are yet to be unravel. In this report, we describe the results of our preliminary analysis of a cohort of hospitalized pediatrics COVID-19 patients focusing on mode of presentation, presence of comorbidities, severity of disease, and early outcome.
MATERIALS AND METHODS
We conducted a multicenter retrospective analysis of clinical record of SARS-CoV-2-infected children in 23 different sites in Italy.
From February 21, 2020, to May 1, 2020, subjects less than 18 years of age with a positive result on high throughput sequencing or real-time reverse transcriptase-polymerase chain reaction assay of nasal/pharyngeal swab specimens were included.
The study was approved by the ethical committees of the coordinating center in Milan (protocol number 2020/ST/061).
Data regarding recent exposure history, clinical symptoms or signs, and laboratory findings on admission were extracted using a common clinical record form. Radiologic assessments and laboratory testing were performed according to the clinical care needs of the patient.
The Student’s t test, the χ2 method, and Fisher’s exact test were used as appropriate for statistical analysis to compare continuous and categorical variables. A P value <0.05 was chosen as cutoff for significance. Data were analyzed with StataMed (version 12.0).
RESULTS
Overall, 127 children were included; 44 were female (34.9%) and the median age was 4.8 years (interquartile range, 0.3–8.5); 57 (45%) <12 months of age.
Eight of 127 (6.7%) were admitted in ICU, 14 of 127 (12%) required oxygen therapy, 5 (4%) were noninvasive ventilation, and 1 patient required mechanical ventilation during the hospitalization.
The severity of the COVID-19 in our children was defined using previously published criteria3; 7.9%, 48.8%, and 27.7% of their clinical features were defined respectively as asymptomatic, mild, or moderate accounting for 84.4% of our cohort; 8.7% was severe and 7.1% was critical.
Age class, sex, and ethnic group did not show a different distribution among the severity categories (P = 0.57, 0.62, and 0.375 Fisher exact test; Table 1).
TABLE 1. -
Association of Clinical Characteristics With Severity Score and ICU
| Characteristics |
Asymptomatic, mild, or moderate |
Severe or critical |
P
a
|
Not ICU |
ICU |
P
a
|
| N = 107 |
N = 20 |
N = 111 |
N = 8 |
| N |
% |
n |
% |
N |
% |
n |
% |
| Age median (IQR, y) |
1.6 (0.3, 7.9) |
4.3 (0.3, 10.1) |
0.393b
|
1.6 (0.3, 7.9) |
5.5 (0.4, 10.1) |
0.497b
|
| Age group |
|
|
|
|
0.845 |
|
|
|
|
0.854 |
|  Newborn |
5 |
4.7 |
1 |
5.0 |
|
6 |
5.4 |
0 |
0.0 |
|
|  Infant |
44 |
41.1 |
7 |
35.0 |
|
44 |
39.6 |
3 |
37.5 |
|
|  Children |
42 |
39.2 |
8 |
40.0 |
|
46 |
41.4 |
3 |
37.5 |
|
|  Adolescent |
16 |
15.0 |
4 |
20.0 |
|
15 |
13.5 |
2 |
25.0 |
|
| Male |
68 |
64.2 |
14 |
70.0 |
0.799 |
71 |
64.5 |
5 |
62.5 |
1.000 |
| Presentation |
|
|
|
|
|
|
|
|
|
|
|  Fever |
85 |
79.4 |
20 |
100.0 |
0.023 |
92 |
82.9 |
8 |
100.0 |
0.352 |
| Respiratory symptoms |
68 |
63.6 |
14 |
70.0 |
0.799 |
74 |
67.3 |
4 |
50.0 |
0.441 |
|  Respiratory symptoms only |
46 |
43.0 |
7 |
35.0 |
0.624 |
44 |
39.6 |
2 |
25.0 |
0.468 |
|  Cough |
52 |
48.6 |
9 |
45.0 |
0.812 |
57 |
51.4 |
2 |
25.0 |
0.812 |
|  Rhinorrhea |
43 |
40.2 |
6 |
30.0 |
0.460 |
46 |
41.4 |
0 |
0.0 |
0.022 |
|  Wheezing |
4 |
3.7 |
0 |
0.0 |
1.000 |
3 |
2.7 |
0 |
0.0 |
1.000 |
|  Dyspnea |
5 |
4.7 |
5 |
25.0 |
0.009 |
7 |
6.4 |
2 |
25.0 |
0.114 |
| GI symtomps |
26 |
24.3 |
10 |
50.0 |
0.029 |
31 |
27.9 |
4 |
50.0 |
0.232 |
|  GI symptoms only |
13 |
12.1 |
5 |
25.0 |
0.160 |
14 |
12.6 |
3 |
37.5 |
0.087 |
|  Vomit |
6 |
5.6 |
6 |
30.0 |
0.004 |
6 |
5.4 |
6 |
75.0 |
0.004 |
|  Diarrhea |
20 |
18.7 |
8 |
40.0 |
0.044 |
20 |
18.0 |
8 |
100 |
0.044 |
|  Abdominal pain |
6 |
5.6 |
2 |
10.0 |
0.611 |
8 |
7.2 |
0 |
0.0 |
1.000 |
| Comorbidities |
14 |
13.1 |
6 |
30.0 |
0.088 |
16 |
14.4 |
3 |
37.5 |
0.115 |
|  Chronic cardiac conditions |
3 |
2.8 |
2 |
10.0 |
0.176 |
4 |
3.6 |
1 |
12.5 |
0.298 |
|  GI disorder |
2 |
1.9 |
2 |
10.0 |
0.117 |
2 |
1.8 |
1 |
12.5 |
0.190 |
|  Obese |
1 |
0.9 |
2 |
10.0 |
0.064 |
3 |
2.7 |
0 |
0.0 |
1.000 |
|  Chronic kidney disease |
2 |
1.9 |
0 |
0.0 |
1.000 |
2 |
1.8 |
0 |
0.0 |
1.000 |
|  Chronic neurologic disease |
0 |
0.0 |
2 |
10.0 |
0.024 |
1 |
0.9 |
0 |
0.0 |
1.000 |
|  Immunologic condition |
2 |
1.9 |
0 |
0.0 |
1.000 |
1 |
0.9 |
0 |
0.0 |
1.000 |
| CXR positive |
25 |
43.9 |
13 |
65.0 |
0.125 |
35 |
51.5 |
3 |
37.5 |
0.711 |
| Complication |
23 |
21.5 |
19 |
95.0 |
<0.001 |
35 |
31.5 |
7 |
87.5 |
0.003 |
|  Viral pneumonia |
16 |
15.0 |
9 |
45.0 |
0.004 |
24 |
21.6 |
1 |
12.5 |
0.468 |
|  Bronchiolitis |
8 |
7.5 |
1 |
5.0 |
0.570 |
9 |
8.1 |
0 |
0.0 |
0.522 |
|  Bacterial pneumonia |
0 |
0.0 |
2 |
10.0 |
0.024 |
1 |
0.9 |
1 |
12.5 |
0.130 |
|  ARDS |
0 |
0.0 |
2 |
10.0 |
0.024 |
1 |
0.9 |
1 |
12.5 |
0.130 |
| Pleural effusion |
0 |
0.0 |
1 |
5.0 |
0.157 |
0 |
0.0 |
1 |
12.5 |
0.067 |
|  Myocardial involvement |
0 |
0.0 |
6 |
30.0 |
<0.001 |
2 |
1.8 |
4 |
50.0 |
<0.001 |
|  Bacteremia |
0 |
0.0 |
1 |
5.0 |
0.157 |
0 |
0.0 |
1 |
12.5 |
0.067 |
|  Coagulation disorder |
0 |
0.0 |
1 |
5.0 |
0.157 |
0 |
0.0 |
1 |
12.5 |
0.067 |
|  AKI |
0 |
0.0 |
1 |
5.0 |
0.157 |
0 |
0.0 |
1 |
12.5 |
0.067 |
|  Liver dysfunction |
0 |
0.0 |
1 |
5.0 |
0.157 |
0 |
0.0 |
1 |
12.5 |
0.067 |
|  Myositis |
1 |
0.93 |
0 |
0.0 |
0.843 |
1 |
0.9 |
0 |
0.0 |
0.933 |
AKI indicates acute kidney injury; ARDS, acute respiratory distress syndrome; CXR, chest radiograph; GI, gastrointestinal; ICU, intensive care units; IQR, interquartile range.
Twenty of 127 patients (15.7%) had at least 1 comorbidity. Five (3.9%) had chronic cardiac condition, 4 (3.1%) had gastrointestinal (GI) disorder, 3 (2.4%) were obese, 2 (1.6%) had chronic kidney disease, chronic neurologic disorder, and immunologic condition, respectively. Only 1 medically complex patient (defined as children who required long-term dependence on life support) was included. Comorbidities distribution was not different among severity classes (P = 0.08 Fisher exact test). Moreover, the ICU admission rate was similar in patients with comorbidities and those without (P = 0.115 Fisher exact test).
The most common symptoms reported on admission were fever (82.7%), cough (48%), and rhinorrhea (38%). Seventy-seven of 127 (60.6%) presented with respiratory symptoms (cough, rhinorrhea, wheezing, and dyspnea).
Thirty-six out 127 (28.3%) had GI symptoms (vomit, diarrhea, abdominal pain), of them twenty-eight (22%) had diarrhea, 12 (9,4%) vomit, and 8 (6.3%) abdominal pain.
The presence of GI symptoms at the admission was differently distributed throughout severity classes (P = 0.006). Having GI symptoms was more frequently associated with severe and critical phenotype (P = 0.029). Interestingly, a history of GI symptoms was positively associated with cardiac involvement as clinical complications, in presence of other symptoms (P = 0.007) or alone (P = 0.004).
Roughly, a third of the children presented lower respiratory tract complications as viral pneumonia and bronchiolitis. Viral pneumonia was more frequently reported in severe phenotype (P = 0.004), while admission rate to ICU was equally distributed among these patients. Chest radiogram was performed in 77 patients (65%) on admission, and infiltrates were found in 38 of 77 (50%). Respectively, 20 and 15 patients had bilateral and monolateral infiltrates, for 3 of them it was not specified. In 4 of 77 (5.2%), atelectasis and pleural effusion were found. The presence of infiltrates at the chest radiogram did not correlate with severity clinical score or ICU admission rate (P = 0.125 and 0.71 Fisher exact test, respectively).
DISCUSSION
In the present study, we reported that most SARS-CoV-2-infected children had fever and respiratory symptoms. Similarly, Shekerdemian et al4 reported that most of the patients included in the North American Pediatric Intensive Care Unit cohort presented respiratory symptoms, but they also state that only 1 child of their cohort presented GI symptoms, speculating that these may be associated with milder clinical presentation.
In children, common circulating human coronaviruses can cause GI symptoms in up to 57% of cases, and this presentation is more common in children than adults.5 Increasing evidence showed that the GI tract may represent a target for SARS-CoV-2 due to the expression of the angiotensin-converting enzyme 2, a major virus receptor. We reported, differently to published data, that a history of gastrointestinal (GI) was positively correlated with a worst severity score (severe and critical) and a higher ICU admission rate. The same result was found, in an pooled analyses of adult cohorts, where GI were correlated to increased odds of critical disease and higher prevalence of complications.6
Interestingly, in our cohort having GI was more frequently reported in patients who developed cardiac impairment as complications of SARS-CoV-2 infection. The development of hyperinflammatory syndromes and Kawasaki-like disease in children exposed to SARS-CoV-2 infection has been recently brought to attention. Riphagen et al7 reported 8 cases of hyperinflammatory syndrome with cardiac involvement, all of them presenting with fever and significant GI symptoms (diarrhea, vomit, abdominal pain), according to our current results and to what we have previously reported.8
In recent studies,4,9 comorbidities have been frequently reported in patients requiring admission to ICU. In the North American Pediatric Intensive Care Unit cohort, authors reported that up to 80% of patients included had comorbidities. The most common comorbidity reported was medically complex defined as long-term dependence on technologic support.4 In agreement with this cohort, Parri et al, in a SARS-CoV-2 positive cohort of pediatric patients admitted at Italian Emergency Departments, reported that 9 patients of 100 need mechanical ventilation and, among them, 6 (66%) had comorbidities.9
In the present study, only 20 (16%) children with previous medical condition were included, 3 of them required ICU. The presence of preexisting medical conditions was not different in severe and critical patients when compared with mild, moderate, and asymptomatic ones. Moreover, the ICU admission rate was similar in patients with and without comorbidities.
There are several limitations to our study. First, the limited sample size. Second, children have been classified using a severity score previously applied to other pediatric cohorts, which is mainly designed on respiratory symptoms and lung involvement. The score criteria could explain the higher frequency of viral pneumonia among severe phenotype but not among patients requiring ICU admission. However, critical cases are defined not only by the progression to respiratory failure (acute respiratory distress syndrome) but also to life-threating organ dysfunction (shock, myocardial injury, acute kidney injury). Therefore, in the present study, the subset of critical patients includes not only patients with respiratory failure but also with other life-threating conditions. Finally, there are evidences that COVID-19-related multisystemic inflammatory syndrome could be a complication in the disease spectrum. Although a better understanding of timing between GI and its onset would be of great interest, we could not provide such information in the current study.
CONCLUSIONS
The intention of this short report is to bring to attention that COVID-19 disease spectrum in children is far from been described in a universally shared way. Other manifestations from respiratory are often the cause of severe illness, as we reported. Having preexisted medical conditions is not associated with worse outcome and consequently, severe clinical presentation must be considering also in previously healthy children.
GI symptoms seem to be a clinical warning for children evaluated in any clinical settings when SARS-CoV-2 infection is suspected, independently of comorbidities.
Pathogenetic mechanisms causing severe phenotypes in SARS-CoV-2-infected children need to be deepened by multidisciplinary approach as well we need more data to define a suitable clinical severity score for COVID-19 in children.
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