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Pneumonia in Hospitalized Children During SARS-CoV-2 Pandemic. Is it All COVID-19? Comparison Between COVID and Non-COVID Pneumonia

Jimenez-García, Raquel MD, PhD*; Nogueira, Javier MD; Retuerta-Oliva, Azucena MD*; Sainz, Talía MD, PhD†,‡,§; Cano-Fernández, Julia MD*; Flores-Pérez, Patricia MD*; Méndez-Echevarría, Ana MD, PhD†,‡,§; Villalobos-Pinto, Enrique MD*; Calleja-Gero, Lourdes MD*; Sanz-Santaeufemia, Fancisco J. MD*; Romero, María P. MD, PhD; del Rosal, Teresa MD, PhD†,‡,§; Baquero-Artigao, Fernando MD†,‡,§; Grasa, Carlos MD†,‡,§; Calvo, Cristina MD, PhD†,‡,§

Author Information
The Pediatric Infectious Disease Journal: March 2021 - Volume 40 - Issue 3 - p e111-e113
doi: 10.1097/INF.0000000000003008
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Abstract

Although the course of the infection is generally milder in children than in adults, pediatric SARS-CoV-2 can also cause pneumonia, eventually requiring hospitalization.1–3 Clinical characteristics of SARS-CoV-2 associated pneumonia in children are not well established. During the COVID-19 pandemic, most cases of pediatric pneumonia were considered possibly attributable to SARS-CoV-2, even those lacking etiologic confirmation.1 Polymerase chain reaction (PCR) remains the gold standard for diagnosis, but its sensitivity and specificity in children is not well defined. There is an increasing interest in the role of serologic tests, as the improvement of sensitivity and specificity would lead to a better characterization of the disease4,5 and help to identify patients who were not diagnosed by PCR.

Due to the health care system overload during the pandemic, only 2 tertiary hospitals were designated for pediatric hospitalization in Madrid, Spain. We describe the clinical and microbiologic characteristics of children admitted with pneumonia during the first wave of the pandemic in these 2 hospitals that centralized all pediatric admissions.

PATIENTS AND METHODS

All children <16 years of age who were admitted for radiologically confirmed pneumonia in 2 university hospitals during the lockdown, between March 1 and May 15, 2020, were included in the study. During this period schools were closed and children stayed at home. A 1-hour daily walk was permitted starting from May. The study was approved by the local Ethics Committee. Serology testing for SARS-CoV-2 IgG was performed during follow-up together with a clinical questionnaire to screen for new symptoms after discharge.

All children admitted with a diagnosis of community-acquired pneumonia confirmed by a radiologist were included. Patients with an underlying onco-hematologic disease or that fulfilled criteria of Pediatric Inflammatory Multisystem Syndrome Temporally associated with SARS-CoV-2 were excluded.

Pneumonia was classified as typical if it fulfilled 3 or more of the following criteria: fever >38 °C, focal consolidation, leukocytes >15,000/mm3, neutrophils >10,000/mm3, C-reactive protein >5 mg/dL or procalcitonin >2 ng/mL. The rest were considered atypical.

Cases with a positive PCR by nasopharyngeal swab during admission and those with positive SARS-CoV-2 IgG performed at least 6 weeks after admission were considered SARS-CoV-2 associated pneumonia.

SARS-CoV-2 PCR (Vircell; sensitivity 96%, specificity 100%) was performed by nasopharyngeal swab sample at admission. Serologic tests included a rapid immunochromatography test (All Test Rapid 2019-nCoV IgG/IgM Lateral Flow Immunoassay) in one of the hospitals and chemiluminescence (Abbott or Vircell) in the other. Blood cultures were obtained in all patients. Additional microbiologic studies were carried out according to the physician’s criteria, including PCR for Bordetella pertussis and other respiratory viruses, and Mycoplasma pneumoniae or Chlamydia pneumoniae serology.

Qualitative data were expressed as absolute and relative frequencies and quantitative data as median and interquartile range (IQR). Categorical variables were compared using χ2 and Fisher exact test and continuous variables with Student t test or nonparametric tests, as appropriate. A 2-tailed value of P < 0.05 was considered statistically significant. All analyses were performed using the Statistical Package for the Social Sciences, version 21.0 (IBM Corp., New York, CA).

RESULTS

A total of 111 children were included in the study; median age was 33 months (IQR: 13–82); 49.5% were male and 15% had underlying medical conditions (mainly neurologic). The most common symptoms were fever (106/111; 96.5%), cough (98/111; 88%) and breathing difficulty (63/111; 56.8%). Two-thirds of the patients (66.6%) had oxygen saturation below 93%. The chest radiograph showed lobar consolidation in 65 (68%), ground-glass interstitial pattern in 30 (27%) and perihilar infiltrates in 16 cases (14%) with bilateral involvement in 43 cases (38.7%). Sixty-six cases were classified as atypical pneumonia (59.5%) and the remaining 45 cases (41.5%) as typical.

Detection of SARS-CoV-2 by PCR testing was performed on all but 4 patients, with positive results in 19/107 cases (17.7%). The SARS-CoV-2 serologic study was accepted and performed on 98/111 (88%) participants, a median of 75 days after admission (IQR: 56–86), and 18/98 of these participants (18.3%) were positive for IgG. A total of 78% (14/18) of children with positive PCR on admission were IgG-positive, and 22% (4/18) of these children did not seroconvert. Eighty of the 88 patients with negative PCR underwent serology testing. IgG was positive in 4 children (5%) but none of them reported new symptoms after discharge. Finally, 23 cases (20%) were considered attributable to SARS-CoV-2. A bacterial agent was identified in 19 cases (17%). PCR for respiratory viruses was carried out on 25 children, with 11 (44%) testing positive. Coinfections with SARS-CoV-2 were detected in 4/23 (17%) patients: (1) Streptococcus pneumoniae, (2) Mycoplasma pneumoniae, (3) Bordetella pertussis and Mycoplasma and (4) adenovirus.

Results of the microbiologic studies suggested a probable etiology in 47 cases (42%): 23 SARS-CoV-2 related, 11 Mycoplasma (excluding coinfections with SARS-CoV-2), 2 S. pneumoniae, 1 S. pyogenes and 10 respiratory viruses.

A comparison was made (Table 1) between COVID-19 confirmed pneumonia (n = 23) and other etiologies (n = 76) with SARS-CoV-2 reasonably ruled out (negative PCR and serology). Most of COVID-19 cases were older and had a more frequently confirmed household contact. Vomiting, headache and asthenia were associated with SARS-CoV-2. Rhinorrhea, anosmia and abdominal pain were infrequent in children with COVID-19. No significant differences in radiologic pattern were identified. Up to 17% of children with COVID-19 pneumonia (4 cases) presented with pleural effusion and one of them a coinfection with S. pneumoniae. This patient and another with single SARS-CoV-2 infection and pleural effusion were admitted to pediatric intensive care unit. Lymphopenia and thrombopenia were significantly associated to COVID-19, however, no increase in D-dimer levels was observed. The duration of oxygen therapy was longer in COVID-19 associated pneumonia (P = 0.023) but we found no differences in length of hospital stay. None of the patients died.

TABLE 1. - Characteristics of Hospitalized Children With SARS-CoV-2 Pneumonia Vs. Other Pneumonias (SARS-CoV-2 Serology and PCR Negative)
COVID-19 (n = 23) No-COVID (n = 76) OR (95% CI) P
Male sex 15 (65%) 36 (47%) 0.085
Median age in months (IQR) 115 (22–149) 32 (15–68) 0.007
Confirmed SARS-CoV-2 household contact 8 (34.7%) 10 (13%) 3 (1.008–9.4) 0.045
Underlying conditions 4 (17%) 12 (15.7%) 0.789
Signs and symptoms
 Temperature >37.9 °C 23 (100%) 72 (94.7%) 0.272
 Cough 20 (87%) 68 (89%) 0.684
 Rhinorrhea 10 (43%) 51 (67%) 2.2 (1.08–4.8) 0.026
 Odynophagia 3 (13%) 5 (6.5%) 0.287
 Breathing difficulty 11 (48%) 45 (59%) 0.252
 Vomiting 10 (43%) 15 (19.7%) 2.8 (1.01–7.8) 0.042
 Diarrhea 6 (26%) 11 (14%) 0.337
 Headache 6 (26%) 3 (3.9%) 7.1 (1.5–32) 0.005
 Abdominal pain 0 12 (15.8%) 0.74 (0.65–0.84) 0.047
 Myalgia 3 (13%) 3 (3.9%) 0.095
 Asthenia 4 (17%) 6 (7.9%) 6.7 (1.7–26) 0.003
 Rash 3 (13%) 3 (3.9%) 0.095
 Anosmia 2 (8.6%) 1 (1.3%) 0.060
 Hypoxia 14 (60%) 52 (68%) 0.224
Chest radiograph
 Perihilar infiltrates 3 (13%) 12 (15.8%) 0.484
 Ground glass interstitial pattern 8 (34.7%) 18 (23.6%)
 Lobar consolidation 12 (52%) 46 (60%)
 Pleural effusion 4 (17%) 11 (14%) 0.671
Blood tests
 Leukocytes/mm3 (IQR) 9010 (5830–15,300) 12,255 (7932–15,792) 0.012
 Lymphocytes/mm3 minimum (IQR) 1222 (810–2890) 2320 (1540–3805) 0.063
 Lymphopenia according to the normal value for age 12 (52%) 21 (27.6) 0.047
 Platelets/mm3 (IQR) 267,000 (174,000–410,000) 340,000 (274,000–454,500) 0.003
 D-dimer, mg/dL (IQR) maximum 1145 (722–2154) 920 (710–2112) 0.135
 PCT, ng/mL (IQR) maximum 0.17 (0.07–0.78) 0.27 (0.07–1.17) 0.539
 CRP, mg/dL (IQR) maximum 3.7 (1.1–10.3) 3.7 (1.5–7.5) 0.743
Pneumonia classification*
 Atypical 16 (70%) 44 (58%) 0.385
 Typical 7 (30%) 32 (42%)
Treatment
 Hydroxychloroquine 13 (56%) 9 (11.8%) 0.0001
 Azithromycine 14 (60.8%) 24 (31.5%) 0.019
 Corticosteroids 4 (17%) 16 (21%) 0.769
 Salbutamol 7 (30%) 28 (36.8%) 0.406
 Remdesivir 1 0
Outcome
 Total days of fever 7 (2–13) 5 (2.2–6) 0.080
 Days of oxygen 4 (2–6) 2.5 (1–3) 0.023
 Days of admission (IQR) 4 (2–7) 3 (2–4) 0.185
 PICU admission 2 (8.6%) 2 (2.6%) 0.178
*Typical bacterial pneumonia was considered if 3 or more criteria of: fever >38 °C; focal consolidation; leukocytes >15,000/mm3; neutrophils >10,000/mm3; CRP >5 mg/dL or PCT >2 ng/mL. The rest were considered atypical.
CRP, C-reactive protein; PICU, pediatric intensive care unit; OR, odds ratio; CI, confidence interval; PCT, procalcitonin.
Significant results are marked in bold.

DISCUSSION

Our study describes a series of children hospitalized with pneumonia during the lockdown of the COVID-19 pandemic. Only 20% of cases were attributable to SARS-CoV-2: these cases were characterized by older age, presence of headache, vomiting, lymphopenia and thrombopenia. The serology helped to detect 4% of cases, a relatively small percentage. Although we cannot rule out the possibility of acquiring the infection after discharge and before serology was performed, the patients did not report new symptoms. We believe the data most likely demonstrate the existence of false-negative PCR in relation to different factors such as swab technique, the type and quality of specimen obtained or the viral load at the time of testing.6 Retesting highly suspicious cases are therefore recommended. In 20% of patients with positive PCR on admission, no IgG antibodies were detected. Although a rapid decrease in antibody titers has been described,7 serologic testing was performed at a median of 75 days after hospital admission, which seems a rather short period of time to expect the total clearance of antibodies. The true sensitivity and specificity of serologic tests in children and the duration of antibodies are uncertain.8 As previously suggested, the development of a specific T-cell response in the absence of seroconversion could explain these findings.9

Our data highlights that, other respiratory viruses and bacteria were common during one of the strictest lockdowns in Europe and with widespread transmission of SARS-CoV-2 and therefore not all pneumonia should be attributed to SARS-CoV-2. Coinfections are not infrequent10; up to 17% of COVID-19 pneumonia had coinfections in our series, and this should be ruled out. Pandemic waves will most probably coexist with other common viral infections in children, such as RSV or influenza. To address clinical, radiologic and analytical parameters is key to differentiate COVID-19 pneumonia from other etiologies. Our results suggest that clinical signs and symptoms of SARS-CoV-2 associated pneumonia in children are unspecific. To distinguish it from other viral infections is challenging and although children with COVID-19 pneumonia were older and vomiting, asthenia and headache were more frequent symptoms. Lymphopenia and thrombopenia may also be a key finding in diagnostic suspicion, as well as a history of exposure as previously described.3 Segmental consolidations, parenchymal infiltrates and pleural effusion were common, without significant differences between groups. This data along with previous publications,11 suggest that the specificity of chest radiograph is low for COVID-19 identification. While there is consensus that chest CT is not justified in children, the role of thoracic ultrasound has yet to be defined.

Our study has limitations: the retrospective design, the relatively small sample size and the restrictions in microbiologic tests due to the laboratories’ overload during the pandemic. However, our study includes practically all the hospitalizations due to pneumonia in children in our city, given the unique situation during the pandemic.

In conclusion, in this series of children admitted with pneumonia during the first pandemic wave in our country, only 20% of cases were finally attributable to SARS-CoV-2 infection. Etiologies other than SARS-CoV-2 were common despite the lockdown. Children with COVID-19 pneumonia were frequently older and typically presented with headache, vomiting and asthenia. Lymphopenia and thrombopenia were usually associated, but D-dimer levels did not increase. The health outcome was generally good.

ACKNOWLEDGMENTS

We thank Claire Marsden and Kinga Amália Sándor-Bajusz for the revision of the English language.

REFERENCES

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Keywords:

COVID-19; SARS-CoV-2; pneumonia; children; serology

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