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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 9  |  Issue : 4  |  Page : 131-138

Epidemiology, clinical presentation, and respiratory sequelae of severe adenoviral pneumonia in children admitted in a tertiary care pediatric intensive care unit from Eastern India: A single-center observational study


1 Department of Pediatrics, Institute of Child Heath, Kolkata, West Bengal, India
2 Department of Medical and Molecular Microbiology, Institute of Child Heath, Kolkata, West Bengal, India

Date of Submission17-Mar-2022
Date of Decision03-Jun-2022
Date of Acceptance18-Jun-2022
Date of Web Publication20-Jul-2022

Correspondence Address:
Dr. Argha Rajbanshi
Institute of Child Health, Kolkata, 700017, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpcc.jpcc_84_21

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  Abstract 


Background: Adenovirus affects mainly the respiratory system, leading to life-threatening pneumonia. This study was aimed to describe the epidemiological, clinical, biochemical, and radiological profile and respiratory sequelae during follow-up among children with severe adenoviral pneumonia (ADVP) admitted in a tertiary care pediatric intensive care unit (PICU).
Subjects and Methods: This is a single-center, prospective study conducted in PICU from eastern India from December 2018 to August 2021. Children less than 10 years of age, admitted with features suggestive of lower respiratory tract infection (LRTI)/pneumonia and positive for adenovirus by respiratory polymerase chain reaction during the study period were included. All children were managed symptomatically. Antibiotics were used in all children and respiratory support was given according to the severity as per standard management protocol.
Results: Among 96 children with adenoviral pneumonia, 33 (34.4%) had severe ADVP and required PICU care. Among them, 28 (84.8%) were males and 24 (72.7%) had SPO2 <90% at the time of admission. Twenty (60%) children needed some respiratory support beyond simple oxygen therapy. Among 33 children, 9 (27.3%) died, 2 left against medical advice, and 22 (66.7%) survived and were discharged. Among discharged, 2 (9%) were lost in follow-up and 20 (91%) children were followed up for the next 2.5 years. During the follow-up, 18 (90%) had recurrent symptoms, and high-resolution computed tomography showed features suggestive of postinfective bronchiolitis obliterans in most of them.
Conclusions: Unlike other respiratory viruses, ADVP had a longer course of illness, seemed to be more severe, and had more long-term sequelae.

Keywords: Adenoviral pneumonia, HHFNC, postinfective bronchiolitis obliterans


How to cite this article:
Rajbanshi A, Giri PP, Laha S, Poddar S. Epidemiology, clinical presentation, and respiratory sequelae of severe adenoviral pneumonia in children admitted in a tertiary care pediatric intensive care unit from Eastern India: A single-center observational study. J Pediatr Crit Care 2022;9:131-8

How to cite this URL:
Rajbanshi A, Giri PP, Laha S, Poddar S. Epidemiology, clinical presentation, and respiratory sequelae of severe adenoviral pneumonia in children admitted in a tertiary care pediatric intensive care unit from Eastern India: A single-center observational study. J Pediatr Crit Care [serial online] 2022 [cited 2022 Dec 6];9:131-8. Available from: http://www.jpcc.org.in/text.asp?2022/9/4/131/351522




  Introduction Top


Human adenovirus is an important cause of febrile illness affecting mainly the respiratory system ranging from pharyngitis, coryza to fatal pneumonia. It also affects other systems causing gastrointestinal, hepatological, ophthalmic diseases. Most of the infections result in complete recovery but may result in considerable morbidities and mortalities in selected children who developed adenoviral pneumonia (ADVP).[1],[2],[3],[4]

ADVP may present as a bronchiolitic illness with predominantly wheezy symptoms or like bronchopneumonia or lobar consolidation and may progress to develop acute respiratory distress syndrome (ARDS).[5],[6],[7] Life-threatening severity is mainly noted in children with impaired T cell immunity but recently many reports had been published all over the world where apparently immunocompetent kids had been affected by severe ADVP.[4],[5] Another unique feature of ADVP is that even after the resolution of the acute phase, a significant number of severe cases develop a chronic form of it with persistent wheezing with waxing and waning symptoms needing continuous or intermittent respiratory support and oxygen supplementation and developed post infective bronchiolitis obliterans (PIBO) or bronchiectasis. A Malaysian study reported PIBO in 22% of cases.[1],[4]

In this study, we concentrated mainly on the sickest cohort of ADVP who needed pediatric intensive care unit (PICU) care and tried to explain that ADVP can be severe in immunocompetent children tried to establish a pattern of severe disease, explained intensive management done in PICU and development of sequela.


  Materials and Methods Top


This is a single-center, prospective study conducted at the tertiary care pediatric intensive care unit from Eastern India, and included all children aged < 10 years, admitted to PICU of the hospital with laboratory-confirmed adenoviral lower respiratory tract infection (LRTI)/ADVP between December 1, 2018 and May 1, 2019 to describe the epidemiological, clinical, biochemical, and radiological profile; and respiratory sequelae. Incidence of viral infection is more in lower age and hospital admission is less in old children.

Ethical clearance and consent

Ethical approval for this study was obtained from the institutional ethics committee (No: ICH/IECBMHR/13/2022). Verbal and written consent was taken from the patient's parents. Questionnaires were given to the parents whose children were followed up.

Nasopharyngeal swab in nonintubated children and bronchoalveolar lavage fluid from intubated children had been collected. Real-time multiplex polymerase chain reaction (PCR). SpinStar™ Pathogen Nucleic Acid Kit 1.0 is used for nucleic acid extraction and RespiFinder® 2SMART is used to perform multiplex reverse transcription PCR in Rotor-Gene Q of Qiagen following manufacturer's guidelines.

Data collection was done from PICU during patient admission, stay, and during follow-up in the study period. History, findings during admission including vitals and the need for respiratory support, laboratory findings, and conditions during follow-up were noted.

For statistical analysis, proportions, and means (standard deviation [SD]) will be calculated for categorical and continuous variables by the vital status of the children. Univariable regression analyses will be done to measure the association between demographic, clinical, laboratory, and radiological variables with mortality. For binary outcomes, generalized linear models (GLMs) of the binomial family with a log-link function will be used to calculate the effect size (relative risk [RR] and 95% confidence interval [CI]). For continuous outcomes, GLMs of the Gaussian family with an identity-link function will be used to calculate the effect size (difference in means and 95% CIs). We used STATA version 16 (Stata Corporation, College Station, TX, USA) for most statistical analyses.


  Results Top


During the study period, 96 children were admitted to our hospital with adenoviral infection as confirmed by PCR. 33 children were admitted to PICU and included in this study. Male children were more with a male-to-female ratio (3.7:1). Most children belonged to 6 months to 1 year age, with a mean age of 9.7 months and SD of 5.13.

Clinical parameters

None of the children had any premorbid condition and only one child had low birth weight. All of the kids were apparently immunocompetent. Immunoglobulin profile and flow cytometry for CD4 and CD8 done in 3 children who were suspected of immunodeficiency, were normal. The time duration of the first onset of symptoms to presentation to our PICU varies widely. 45.5% presented within 7 days of onset of symptoms, 51.5% within 1 week to 1 month of onset, and 3% presented very late, after 1 month. All children had a fever, cough, and respiratory distress of different severity. There was a history of convulsion during or after admission in 5 cases (15.15%). Altered sensorium was there in 9 children during admission (27.27%). Diarrhea was seen in 5 cases (15.15%).

19 (57.6%) children had SPO2 below 90% on admission. 32 (96.96%) children had chest retractions on admission. 11 children had hepatomegaly and 3 had both Splenomegaly and hepatomegaly [Table 1].
Table 1: Clinical symptoms and examination findings in children with adenoviral infection on admission

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Laboratory markers

We found hemoglobin to be <10 gm% in significant numbers of children (~50%). Total leukocyte count was high in 21 children (63.6%). C-reactive protein (CRP) was raised in almost 66.7% of children (22). Serum sodium level was deranged in 13 children (37.5%). Liver enzymes were deranged in a significant proportion of children (46%). Blood cultures were negative in 26 children (78.78%) during the entire study period. 7 children (21.21%) developed nosocomial sepsis during the PICU stay. A total of 6 kids developed features suggestive of hyperferritinemia with MODS in the course of the illness. Chest x-ray revealed bilateral patchy opacities in 14 children (42.4%), lobar consolidation in 3 children (9.1%) hyperaerated lungs in 14 children (42.4%), and normal in 1 child. Nosocomial sepsis (mainly VAP and CLABSI) is more compared to other studies which may be due to prolonged stay, multiple hospital admission, use of corticosteroids, and invasive and non-invasive ventilation and central lines [Table 2].
Table 2: Laboratory features at the time of pediatric intensive care unit admission

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Treatment modalities and outcome

Twenty-nine (86.2%) children required some sort of respiratory support of which 25 children required invasive ventilation, 2 children were managed only with non-invasive ventilation, and 2 children improved with only HHFNC.

Although there are no guidelines to use corticosteroids, it was used in 24 children (72%) as it has been found useful in ADVP, especially with hypercytokinemia. No antiviral drugs were used in our cohort. All of our children received antibiotics.

There was no fixed treatment protocol and we tried to manage symptomatically. Standard ARDS management protocol with lung-protective ventilation judicious fluid use is followed in frank ARDS cases.

Among these 22 survivors, 2 lost to follow-up, and the rest 20 kids followed up for at least 2.5 years.

Among these 20 children, 2 did well in the follow-up without any recurrence or persistent significant chest symptoms.

Rest 18 developed either recurrent or persistent chest symptoms, 8 of them had been managed on an OPD basis, while the rest 10 needed multiple hospital admission in the last 2.5 years with an average of 3.1 hospital admission per patient per year from June 2019 to July 2020 and then 1.4 hospital admission per patient per year from August 2020 to August 2021, indicating that chest symptoms had regressed over time. 2 children needed some home oxygen therapy for 6 and 8 weeks and another needed home HHFNC followed by home oxygen for 13 months postdischarge.

The exacerbations had been managed on an OPD basis in the rest of 8 children with an average of 3.2 exacerbations/patient/year. 6 children did not have an exacerbation in the last 4 months and were on tapering doses of inhaled corticosteroid.

Fifteen among those with recurrent symptoms underwent high-resolution computed tomography (CT) of the chest during the disease. Twelve (80%) showed features of postinfectious bronchiolitis obliterans, 2 (13.3%) had bronchiectasis and one showed persistent Pneumonia. 5 kids underwent fiber-optic bronchoscopy but did not reveal any significant pathology of the tracheobronchial tree except a mild degree of airway-malacia in 2 (10%) [Table 3] and [Figure 1].
Table 3: Treatment and outcome

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Figure 1: Study flow of the 33 patients with adenovirus pneumonia

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Statistical analysis [Table 4] shows the association between demographic, clinical, laboratory, and radiological parameters with mortality. Duration of illness (β coefficient: 0.02; 95% CI: 0.003–0.03) and chest X-ray with patchy opacities (RR: 9.6; 95% CI: 1.2–76.7) were associated with increased risk of mortality.
Table 4: Association between demographic, clinical, laboratory, and radiological parameters with mortality

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  Discussion Top


Adenovirus has more than sixty serotypes divided into subgroups or subspecies (A to G) which affects mainly the respiratory tract apart from the gastrointestinal, hepatic, and ophthalmic systems. Adenoviral epidemics are seen many times.[4],[8] Adenoviral diseases specially ADVP or adenoviral LRTI are believed to be mostly self-limiting in immunocompetent kids and can cause life-threatening infection only in immunocompromised children. But for the last few years, we came across a lot of case reports and series where we have seen fatal and life-threatening ADVP in otherwise immunocompetent children.[1],[4],[8]

This study on severe ADVP in PICU among immunocompetent kids summarizes their epidemiology, clinical presentation, biochemical parameters, risk factors associated with high mortality, and respiratory sequelae.

Out of 96 diagnosed cases of adenoviral infection, 33 children (34.4%) were severe cases and required PICU care and were included in the study. The severity in our study is higher than studies by Jose et al.[1] and Lim et al.[4] Male children were admitted more as compared to female children, this finding is similar to earlier studies from Malaysia by Lim et al.,[4] Brazil by Elenice et al.,[9] and Taiwan by Chen et al.[10] Most of the children in our study were between age 6 months to 1 year followed by the age group of 1–2 years and <6 months, this data is consistent with the study by Elenice et al.[9] and by Rajkumar et al.[11]

Half of the children had a long history of illness which may be due to severity of adenovirus or coinfection, resulting in repeated admission and resulting in ARDS and long-term sequelae which needed intensive and long-term treatment.

All of the children in our study presented with fever with cough and respiratory distress followed by altered sensorium (27.3%), diarrhea, and convulsions (15%). Severe ADVP is usually associated with a high-grade fever unlike other viral pneumonia or bronchiolitis illness.

Significant numbers of severe ADVP present with leukocytosis and raised CRP, unlike other viral pneumonia. In our cohort, CRP was raised in 67% cases and was extremely high (>100 mg/L) in 2 children. Chen et al. showed leukocytosis in 23% of children and raised CRP in 35.8% of children.[10] Another initial diagnostic point of severe ADVP is the presence of transaminitis. Liver enzymes were deranged in 46% of cases, wherein Taiwanese study[10] almost all cases had normal liver enzymes. More than half of children had anemia which may be due to coexisting iron deficiency as most of them belonged to low socioeconomic families.

Severe ADVP can have different appearances radiologically. It may present with bilateral hyper-inflated lung fields suggestive of air trapping or bilateral patchy opacities suggestive of bronchopneumonia or even can present with typical lobar consolidation mimicking bacterial pneumonia. We found bronchopneumonic presentations had the most severe disease and increased mortality.

Treatment of adenoviral infection in immunocompetent kids is mainly supportive as it is a self-limiting infection[1],[12],[13] but in our study, we have encountered severe ADVP needing PICU care in one-third of children. Almost all children received antibiotic treatment before adenoviral etiology had been confirmed and was continued for the risk of secondary bacterial infection.[14],[15] Most of the severe ADVP needed respiratory support beyond simple oxygen therapy. In our cohort, most children were initially tried with HHFNC or NIV failing of which they were put on invasive mechanical ventilation. During follow-up 1 child required home HHFNC followed by home oxygen for 13 months.[5] Min Jae et al. showed a high rate of respiratory failure[6] similar to our study. Out of 29 children, 25 (86.2%) required invasive mechanical ventilation followed by noninvasive ventilation and high flow nasal cannula, 42% of children required inotropic support. We strongly recommend early initiation of HHFNC or NIV to avoid invasive mechanical ventilation-related adverse effects.

None of our children received any antiviral therapy, as currently there are no consensus guidelines about the use of any antiviral agents in severe adenoviral diseases in immunocompetent kids. There are few isolated case reports and series about the use of antiviral agents in severe ADVP in immunocompetent kids. Ganapathi et al. showed clearing of the viral load from blood with the use of Cidofovir but yet there is no change in mortality.[16] Kim et al. found early use of Cidofovir in severe ADVP had a favorable outcome[17] as compared to previous studies like Barker et al.,[18] Hakim et al.[19] and Dudding et al.[20] where most children who received antiviral including Cidofovir had a poor outcome. Also, there is a case report showing improvement in respiratory distress with the use of oral ribavirin.[21] A newer antiviral agent Brincidofovir lipid ester of cidofovir, less nephrotoxic than cidofovir has been studied and shown to have enhanced in vitro action against adenovirus. We didn't use Cidofovir as it is not easily available in our part of the country and had to be imported at a very high cost. Potential nephrotoxicity had been another concern.

There had been an interest in using corticosteroids in the cases of severe ADVP but still today there are no definitive consensus guidelines and which steroid and which doses to be used had not been clarified. In our study corticosteroids were used in 24 children (72.7%) between the 1st and 2nd week of disease. Takahashi et al. found better relief from respiratory distress in severe ADVP with hypercytokinemia[22] after steroid therapy. Several studies showed the use of steroids especially pulse Iv Methylprednisolone with or without Intravenous Immunoglobulin had a favorable outcome in severe ADVP complicated with hypercytokinemia and hyperferritinemia.[23],[24] In our series, we did not find any significant benefit from corticosteroid use except in hyperferritenemic conditions. A steroid may decrease the fever spikes as well as wheezy symptoms but was not effective to resolve the ARDS part as well as preventing the long-term sequelae.

Out of 33 children, 9 children expired, making our case fatality ratio to be 27.3%, which is almost equal to the study by Lim where mortality was 26.3% in a severe group.[5] Chen reported favorable outcomes with no mortality in their study.[10] Mortality and morbidity in 20%–50% can occur in severe adenoviral infection, especially where the nosocomial infection is involved, it also depends upon the immunity of the host, virulence of viral agents, and presence of risk factors.[4],[10] In our cohort, we have found late presentation, as well as bilateral patchy opacities in chest X-rays, had been associated with poor outcomes.

Adenoviral LRTI is notorious to produce long-term respiratory sequelae in the form of recurrent or persistent wheezing without any significant CT changes or in the form of PIBO or bronchiectasis.[15],[25] In our cohort 81% of the survivors from severe ADVP had sequelae. The percentage of respiratory sequelae in our series is more than other studies, a study from Malaysia had respiratory complications of 22% which they quoted to be much higher than similar previous studies.[4] Lim et al.[4] explained that PICU care, the need for ventilation, and the preexistence of Asthma as risk factors for developing complications and sequelae. Saleh Alharbi et al. from Canada found that preexisting lung conditions may predispose to developing complications especially for developing bronchiectasis[26] but in our study, none had preexisting lung diseases. Adenovirus is one of the common organisms implicated in PIBO.[27] Diagnosis of PIBO should be confirmed by histopathology but usually based on history, clinical, and CT findings as per criteria.[27] There are few serotypes like 3, 5, 7 h, and 21 that have been associated with a higher incidence of PIBO.[28],[29] Treatment of PIBO is limited by the usage of inhaled and systemic steroids, intermittent use of inhaled bronchodilators. Oral hydroxychloroquine and azithromycin both had been used as immunomodulatory in cases of PIBO with mixed results.[30] Azathioprine though used successfully in postlung transplant bronchiolitis obliterans, but use in PIBO in children is limited.[28],[31] Most of the kids in our series with PIBO had been treated with inhaled steroids and bronchodilators as well as with oral Hydroxychloroquine and Azithromycin.

The limitation of our study is the unavailability of serotype analysis and the inability to show the association of certain serotypes with clinical presentation, outcomes, and development of PIBO. Due to the smaller sample size, univariate analysis can't be extrapolated.


  Conclusions Top


Contrary to popular beliefs, adenovirus LRTI/ADVP can be life-threatening in immunocompetent kids too. Nonresolving pneumonia with high-grade temperature along with wheezy symptoms with elevated TLC, CRP, and SGPT should prompt a clinician to suspect ADVP early. Those who presented late with bilateral patchy opacities in Chest X-ray have a bad prognosis. Most severe ADVP, especially those who needed mechanical ventilation in the acute phase develop sequelae in the form of PIBO.

Acknowledgment

Dr, Ranadip Chowdhury, Assistant Director, and Research Scientist, CHRD-SARS, helped in reviewing the manuscript as well as in statistical analysis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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