Role of C-Reactive Protein in Predicting Adenoviral Infections in Children Aged 1 Month to 18 Years

INTRODUCTION

Human adenovirus infections (HAdV infections) are associated with a wide range of respiratory and gastrointestinal (GI) tract symptoms and can cause fatal infections in healthy and immunocompromised patients.^[1] HAdVs are double-stranded DNA viruses, divided into more than 55 distinct serotypes and other “new” genetic variants, classified into seven species (A–G). Some types are associated primarily with respiratory tract diseases, whereas others with gastroenteritis.^[2] In clinical practice, mixed symptoms are often seen. Adenoviruses can be transmitted through respiratory tract secretions, fecal-oral spread, and exposure to infected tissue or blood. Children with respiratory or generalized infections excrete the virus for 3–6 weeks in throat mucosa or stool.^[3] Consequently, HAdVs spread easily among children and people living in high-density areas and can be a serious threat to patients with immunodeficiencies.^[4]

Clinical symptoms of HAdVs include – fever, cough, sore throat, and rhinorrhea. Involvement of the lower respiratory tract by HAdVs – bronchitis, bronchiolitis, and pneumonia can be severe and even fatal. HAdV infection can also be implicated in conjunctivitis, diarrhea, cystitis, myocarditis, cardiomyopathy, and meningoencephalitis (multisystemic involvement). Symptomatic HAdV infections are commonly characterized by high-grade and long-lasting fevers with elevated inflammatory cytokines.^[5] Such recent trends of high C-reactive protein (CRP) with negative bacterial yield were observed in our hospital during a recent outbreak of flu-like illness during our study period. Due to limited data available in South India, this study is taken up to compare the available data in our hospital.

The study aimed to analyze the levels of CRP, complete blood count (CBC), clinical features, and outcome in children with adenovirus infection (GROUP-1) and to compare the same parameters in children with other viral infection (GROUP-2) presenting to a tertiary care hospital.

MATERIAL AND METHODS

This is a hospital-based descriptive study, which was done in an urban tertiary hospital. With the clearance from the Ethical Committee of the Institution, 140 children aged 1 month to 18 years presenting with generalized prodromal symptoms (upper respiratory infection (URI), fever, gastrointestinal (GI) symptoms, sore throat, cough, and conjunctivitis) with/without features suggestive of pneumonia were included in this study who are reported to have pure adenoviral infection (adenoviral group – group 1) and the other group of children with pure other viral infections (non-adenoviral group – group 2) detected in respiratory viral panel. Children with infection of skin or skin structures, bacterial pathogens in nasopharyngeal swab, non-sterile culture from blood or any other normally sterile site, urine culture yielding significant bacteriuria, respiratory viral panel showing bacterial infection coexisting with other viral infections, and children on immunosuppressants or chemotherapy were excluded from the study.

Cases with adenovirus infection were considered if adenovirus is detected in nasopharyngeal swabs by real-time polymerase chain reaction (RT-PCR) method.

Coinfection was defined as the detection of more than one pathogen, including viral, bacterial, or atypical pathogens. Such samples with coinfection are excluded from our study. All the nasopharyngeal swabs sent during our study period, that is, from September 2022 to March 2023, were obtained from our microbiology department, and the data were analyzed. The detection of viruses in the nasopharyngeal swab was done using the qualitative multiplexed TaqMan-based RT-PCR.

CRP levels were identified by the immunoturbidimetry method in the microbiology department of our hospital. CRP assessment was done by the same technician who was blinded to the results of the nasopharyngeal swabs.

Data were collected on the history, clinical features, and examination findings at admission. CRP levels, relevant laboratory investigations, and outcomes were taken in a predesigned case recording form.

RESULTS

A total of 140 patients (70 in the adenoviral group and 70 in the non-adenoviral group) who satisfied our inclusion criteria were taken in our study.

CRP as a predictor

CRP levels were significantly higher in the adenoviral group. The mean CRP levels were 42.5 mg/L (31.48) and 17.19 mg/L (39.31) in group 1 and group 2, respectively, which was statistically significant (P = 0.001) [Table 2].

Table 2: Other investigations and duration of hospitalization

Group					Student independent t-test
	Adeno		Non-adeno
	Mean	Standard deviation	Mean	Standard deviation
CRP levels (mg/L)	42.50	31.48	17.19	39.31	t=4.21 P=0.001 (S)
Total count (per microliter)	9773.86	4190.87	10442.34	4674.99	t=0.89 P=0.38 (NS)
Differential count (neutrophil count)	55.84	20.23	51.20	19.09	t=1.40 P=0.16 (NS)
Differential count (Lymphocyte count)	35.12	19.57	41.61	18.91	t=1.20 P=0.05 (NS)
Duration of hospitalization (in days)	6.07	1.88	5.37	1.70	t=2.31 P=0.02 (S)

CRP: C-reactive protein, S: significant, NS: non-significant

The maximum possible sensitivity of 89 % and specificity of 61% is observed for the CRP with the cutoff of 5.5 mg/L having an area under the curve in the ROC curve [Figure 1]. The level below 5.5 mg/L, the sensitivity is not affected whereas the specificity gets lowered. The total differential (neutrophil and leukocyte) counts were not contributory. When combining the clinical features like conjunctivitis, URI signs (tonsillitis/pharyngitis), and GI symptoms (reported significantly in more proportion among those children with adenoviral infections than those with nonadenoviral infections) [Table 1] along with the CRP cutoff of 5.5 mg/L have sensitivity and specificity 84.71% and 54.17%, respectively. The area under the curve is 78 [Figure 1].

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Figure 1:

Receiver operative characteristic (ROC) curve for C-reactive protein levels (in mg/L).

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PREDICTABILITY OF ADENOVIRAL INFECTION WITH A CUTOFF OF CRP AT 5.5 MG/L

Our predictability of adenoviral infections at a cutoff of CRP (5.5 mg/L) with clinical features such as with conjunctivitis alone, the sensitivity is much higher but when combined with URI (Upper respiratory tract) signs the specificity is more. While with added GI (Gastrointestinal) symptoms along with conjunctivitis and URI signs, the predictability is more sensitive. [Table 3]

DISCUSSION

Human adenovirus (HAdV) is an important cause of respiratory infections in the pediatric population. Human adenovirus infections are one of the most common causes of fever requiring hospital admission when it occurs in younger age groups (<10 years old). The characteristics exhibited by adenovirus were slightly different from those of other viral infections. Our study conducted during the seasonal peak (between September 2022 and March 2023) mainly emphasizes the clinical features, laboratory parameters, and the outcome of proven adenoviral infection. The data are compared with other viral infections (non-adenoviral infections) taking the same parameters. The most frequently ordered outpatient and inpatient blood tests were CRP, CBC, Chest X-ray, and blood and urine culture and sensitivity. Hence, these parameters were taken up for our study to analyze our data. CRP levels in children with adenoviral infection without bacterial coinfection were found to be high. Children with bacterial infection was excluded by taking samples whose blood and urine cultures were sterile and uncomplicated recovery following infection without the need for antibiotics.

In our study, patients presenting with prodromal symptoms followed by a respiratory system infection had a higher CRP level mimicking a bacterial infection. The CRP level traditionally indicates a bacterial infection. Without another etiology explaining the presenting picture, it may result in the initiation of antibiotic therapy. In our study, as already explained, antibiotics were not started as nasopharyngeal swabs yielded viral infections, and negative blood culture was our inclusion criteria. Also, all these children had short, uncomplicated courses of illness and recovery, limiting the use of antibiotics.

In our study, 85.71% of our study group 1 and 74.29 % of study group 2 were in the age group of 1–10 years. In our study, the mean CRP levels of children with adenoviral infection and other viral infections were 42.5 and 17.4, respectively. This clearly states that children with adenoviral infection had higher CRP levels when compared with other bacterial infections. These high CRP levels are attributed to the cytokine storm, which occurs in adenoviral infection. This is in concordance with the study conducted by Appenzeller et al. in the Department of Pediatrics Institute for Infectious Diseases, University of Bern, Inselspital, Bern, Switzerland, where the median CRP in children with adenovirus infection and 130 children with influenza was 49 mg/L and 9 mg/L, respectively. [6] This is also consistent with observations in a study carried out by Kawasaki et al. and other studies,^[7-9] where significantly higher CRP and INTERLEUKIN-6 concentrations were found in children with adenoviral infection when compared to other viral infections (Influenza and respiratory syncytial viruses). In 87 children with an adenoviral infection, CRP levels of <2 mg/L, <10 mg/L, and <100 mg/L were found in 4 (4%), 12 (13%), and 66 (76%) patients, respectively.^[6] In a study conducted by De Oña CG et al.^[10] in the microbiology department, Spain alterations in CRP and procalcitonin were established in patients with adenoviral infections.

Our study has more URI signs (tonsillitis/pharyngitis), conjunctivitis, and GI symptoms in an adenoviral group than in other viral infections (non-adenoviral group). This is similar to a study conducted to analyze the clinical parameters in adenoviral infections where chest retraction and extra-pulmonary manifestations were significantly more common in the adenovirus group, especially conjunctivitis, gastroenteritis, lymphadenopathy, bleeding diathesis, and exanthema.^[11] In our study, the duration of hospitalization was more in the adenoviral group in contrast to studies where there was no difference in the length of hospitalization.^[8,12] In our study, both adenovirus and other viral infections had higher leucocytes levels and higher neutrophil levels. This is in contrast with the findings of a study by Zheng et al.^[9], where cases with adenovirus infection had lower leucocytes levels and higher neutrophil levels than cases without adenovirus infection.

CONCLUSION

CRP levels are significantly higher in the adenoviral group when compared to other viral infection group (Non- nonadenoviral group). While conjunctivitis, GI symptoms, and URI signs (tonsillitis and pharyngitis) significantly more in the adenoviral group, the presence of only conjunctivitis and URI signs has more predictability for adenoviral infection with CRP level cutoff 5.5 mg/L with maximum sensitivity and specificity.