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ORIGINAL ARTICLE

Decreased NK cells in cases of severe adenovirus pneumonia with liver dysfunction in pediatric intensive care unit: Evidence from 330 patients

Yufan Yang, Jiaotian Huang, Haipeng Yan, Xun Li, Ping Zang, Xinping Zhang, Zhenghui Xiao*, Xiulan Lu*

Department of Pediatric Intensive Care Unit of Hunan Children’s Hospital, Changsha, Hunan, China

Yufan Yang and Jiaotian Huang contributed equally to this work.

Abstract

Background: Although the human adenovirus infection is common, adenovirus infection with liver dysfunction is rare.

Methods: To retrospectively analyze and compare the clinical characteristics and outcomes of pediatric patients diagnosed with severe adenovirus pneumonia with and without liver dysfunction, who were admitted to the pediatric intensive care unit of Hunan Children’s Hospital (South China University) between January 2018 and June 2022.

Results: Of the 330 severe adenovirus pneumonia cases analyzed (mean age, 19.88 ± 18.26 months), 102 were girls and 228 were boys. They were divided into two groups: those with liver dysfunction (n = 54) and without liver dysfunction (n = 276). Comparison analysis showed no significant between-group differences in body mass index and levels of white blood cells, neutrophils, platelets, albumin, total bilirubin, direct bilirubin, indirect bilirubin, creatine kinase, procalcitonin, creatinine, and urea nitrogen. However, the levels of alanine aminotransferase (175.99 U/L vs 30.55 U/L) and aspartate transaminase (215.96 U/L vs 74.30 U/L) were significantly higher in patients with liver dysfunction compared to those without liver dysfunction. Further analysis showed that pediatric patients with liver dysfunction had a significantly lower percentage of natural killer (NK) cells (6.93% vs 8.71%) and higher mortality rate (22% vs 9%) than those without liver dysfunction.

Conclusion: A decrease in serum NK cell levels in pediatric patients with severe adenovirus pneumonia could serve as a marker for monitoring the onset or progression of hepatic damage.

Key words: Adenovirus Pneumonia, Liver Dysfunction, Natural Killer Cells

*Corresponding authors: Xiulan Lu and Zhenghui Xiao, Department of Intensive Care Unit, Hunan Children’s Hospital, No. 86 Ziyuan Road, Changsha, Hunan, 410007, China. Email addresses: [email protected]; [email protected]

Received 24 October 2022; Accepted 18 November 2022; Available online 1 May 2023

DOI: 10.15586/aei.v51i3.787

Copyright: Yang Y, et al.
License: This open access article is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/

Introduction

Human adenovirus infection is quite common. Human adenovirus infections comprise at least 5–10% of the infections in children and 1–7% of adult respiratory tract infections (RTI).1 It is mostly self-limiting (within 2 weeks) in immunocompetent patients and typically only causes mild upper respiratory, gastrointestinal, or ocular distress.2,3 Comparatively, immunocompromised patients (10–30% of cases) are at higher risk of severe respiratory failure and mortality.4 Human adenovirus pneumonia has also been reported in 20% of infants and newborns, and in some cases, it might result in deaths of formerly healthy adults or children.5

Liver dysfunction is a rare complication of human adenovirus pneumonia and whether its occurrence is due to direct viral actions on the liver or effects from other extrapulmonary events, that is, systemic inflammation secondary to lung infection, remains unknown. In 2014, Ronan et al.6 were the first to publish a report reviewing the clinical characteristics of adenoviral hepatitis. Since then, there has been no further literature on the clinical assessments of severe adenoviral infections associated with hepatic comorbidities, and Ronan et al.6 focused on data in adult patients, leading to limited evidence on important clinical parameters associated with severe adenovirus pneumonia complications with liver dysfunction in children.

To provide more light on this issue in Chinese settings, we retrospectively analyzed the clinical data of pediatric patients with severe adenovirus pneumonia admitted to the pediatric intensive care unit (PICU) of Hunan Children’s Hospital (South China University) between January 2018 and June 2022. Standard clinical serum biomarkers and status of important immune cell types were reviewed and compared between those with and without liver dysfunction.

Patients and Methods

Patient enrollment

This was an observational, retrospective, single-center study on pediatric patients diagnosed with severe adeno-virus pneumonia between January 2018 and June 2022 at the PICU of Hunan Children’s Hospital (Changsha, China). The exclusion criteria were the presence of concurrent asthma, endotracheal foreign body, any known or suspected active tuberculosis, lung mycosis, pulmonary parasites, ongoing immunodeficiency, or patients receiving immunosuppressants. This study protocol was approved by the Ethics Committee of our hospital.

Adenovirus pneumonia was defined as the presence of a clinician-diagnosed pneumonia and a positive level of adenovirus antigen/IgM antibodies in blood samples (see below). Community-acquired pneumonia was defined as fever and cough, with chest radiographic findings showing lobar or broncho-pneumonia or focal infiltrates.7 The duration of fever (body temperature > 37.5°C) before hospitalization was reported by the caregivers, while the duration after admission was collected from medical records. Based on the definition of community-acquired pneumonia, the diagnosis of severe pneumonia was based on any of the following: sustained high fever (>39°C) for more than 5 days, accompanied by a frequent and severe irritating cough; respiratory rate ≥ 70 breaths/min (infant), or ≥ 50 breaths/min (≥1-year old); severe respiratory failure (PaO2/FiO2 < 250); rapidly progressing lung shadow with multiple- or single-lobar or segment consolidation; a need for mechanical ventilation; and/or a need for intensive care. Admission to ICU was also based on the clinical assessments by the treating pediatric senior medical staff and the presence or potential of clinically significant respiratory distress, dehydration, hypotension, and/or suspicion of encephalopathy.7

The determination of liver dysfunction was based on serological assessment showing total bilirubin levels > 4 mg/dL or levels of alanine aminotransferase (ALT) twice the normal upper limit for the child’s age.8 We excluded the antibiotics influences, different respiratory or hemodynamic problems present in the two groups that may affect the liver function.

Adenovirus detection

Adenovirus was detected via antigen testing of respiratory tract samples, including tracheal aspirates, bronchoalveolar lavage, induced sputum, nose swabs, or nasopharyngeal aspirates. All samples were collected at admission, and the adenovirus antigen was detected using a commercial kit (D3 Ultra DFA Respiratory Virus Screening & ID Immunofluorescence Test Kit, Diagnostic Hybrids, Beijing). Specific IgM antibody assays were also used to confirm the presence of the adenovirus. Briefly, 2 mL of venous blood was drawn at admission, and serum-specific IgM antibodies of common respiratory pathogens were measured using a Respiratory Tract Profile (IgM) indirect immunofluorescence assay (EUROIMMUN Medical Diagnostics, Beijing, China). Other tests for bacteria, viruses, and/or mycoplasma pneumoniae were performed as clinically indicated.

Statistical analysis

The patients’ clinical characteristics, including demographics, laboratory results, and routine blood tests, were obtained from their electronic medical records (Zhong and Dong 2021). Statistical analyses were performed using the SPSS software (v20.0, IBM Corporation, Armonk, NY). Measurement data are expressed as mean ± SD, and cell-type count data as percentages or rates. The chi-square test was used for categorical data analysis. A two-sample t-test and the Mann–Whitney U-test were used for analyses of continuous data. In all cases, P < 0.05 was defined as statistically significant.

Results

General information

Based on the inclusion criteria, a total of 330 children with severe adenovirus pneumonia were included in this retrospective study, among whom 54 (16%) had liver dysfunction complications. The median time lag between severe adenovirus pneumonia diagnosis and liver dysfunction was 2 days (Q1–Q3: 1–4 days). In the 54 children with liver dysfunction, 42 (77.78%) developed liver dysfunction within 72 h after diagnosis of severe adenovirus pneumonia, while the remaining 12 (22.22%) had a slower onset of development (Figure 1).

Figure 1 Distribution of diagnostic time-lags among 54 patients with severe adenovirus pneumonia and liver dysfunction. The figure depicts the median time lag between severe adenovirus pneumonia diagnosis and liver dysfunction, which was 2 days (Q1–Q3: 1–4 days). In the pneumonia with liver dysfunction group (n = 54), 42 (77.78%) patients developed liver dysfunction within 72 h after diagnosis of severe adenovirus pneumonia, while 12 (22.22%) developed liver dysfunction at a later time.

The ratio of boys and girls with liver dysfunction was 2.25:1 (191:85), while that for non-liver dysfunction was 2.18:1 (37:17). The general information and clinical features of the two groups are shown in Table 1.

Table 1 Demographic information for the children in the two groups.

Severe adenovirus pneumonia with
liver dysfunction (n = 54)
Severe adenovirus pneumonia without
liver dysfunction (n = 276)
P
Age (month) 16.28 ± 17.57 20.59 ± 18.34 0.008*
Females (# [%]) 17 [31] 85 [31] 0.921**
BMI 16.39 ± 3.02 15.89 ± 2.33 0.149*
Hospital stay (days) 20.17 ± 15.69 19.36 ± 14.60 0.480*
Ventilator use (# [%]) 23 [43] 101 [34] 0.231*
Mortality rate (# [%]) 12 [22] 25 [9] 0.005**

BMI: Body mass index. *Manne–Whitney U test; **Pearson χ-square test

Values shown are means ± SD

In general, in the group of children with pneumonia but without liver dysfunction, 25 (9%) died over the course of a 28-day postadmission follow-up. In those with liver dysfunction, 12 (22%) died within the 28-day postadmission follow-up. Although not as severe as using survival status (death) as an endpoint, 101 (37%) children in the pneumonia without liver dysfunction group underwent ventilator treatment, while 23 (43%) in the pneumonia with liver dysfunction group required ventilator treatment.

Clinical values

The body mass index (BMI) of the pediatric pneumonia patients with and without liver dysfunction was similar, 16.39 ± 3.02 and 15.89 ± 2.33, respectively. Blood analysis revealed no significant differences in total white blood cell counts and levels of neutrophils, platelets, indirect bilirubin, creatine kinase, creatine kinase isoenzyme, procalcitonin, creatinine, and blood urea nitrogen between the two groups. The laboratory test results are presented in Table 2.

Table 2 Clinical test results for the children in the two groups.

Severe adenovirus pneumonia
with liver dysfunction (n = 54)
Severe adenovirus pneumonia
without liver dysfunction (n = 276)
P
WBC (×109/L) 7.77 ± 5.14 8.80 ± 5.83 0.198*
Neutrophils (×109/L) 4.80 ± 3.63 5.48 ± 4.49 0.383*
Platelets (×109/L) 268.22 ± 148.93 290.52 ± 154.80 0.301*
CK (U/L) 371.84 ± 873.44 249.13 ± 449.38 0.877*
CK-MB (U/L) 28.49 ± 30.56 21.48 ± 14.60 0.064*
Creatinine (μM) 25.24 ± 8.42 27.51 ± 24.39 0.769*
Blood urea nitrogen (mM) 3.06 ± 1.45 3.20 ± 1.69 0.704*
Prothrombin time (PT) (s) 13.82 ± 6.30 12.96 ± 2.09 0.958*
International normalized ratio (INR) 1.10 ± 0.80 1.00 ± 0.24 0.850*
PCT 1.97 ± 3.10 2.41 ± 5.46 0.802*
Albumin (g/L) 32.96 ± 5.45 34.83 ± 4.96 0.013**

CK: Creatine kinase; CK-MB: Creatine kinase isoenzyme; PCT: Procalcitonin; WBC: White blood cells. *Manne–Whitney U test;

**Two-sample t-testValues shown are means ± SD

On the other hand, compared to children with pneumonia but without liver dysfunction, those with liver dysfunction had significantly lower albumin levels (34.83 ± 4.96 g/L vs 32.96 ± 5.45 g/L). In addition, children with liver dysfunction had significantly higher levels of ALT (175.99 ± 310.09 U/L vs 30.55 ± 16.85 U/L) and aspartate transaminase (AST) (215.96 ± 171.34 U/L vs 74.30 ± 58.42 U/L), total bilirubin (16.26 ± 51.02 μM vs 5.65 ± 2.89 μM) and direct bilirubin (5.52 ± 13.40 μM vs 2.21 ± 1.23 μM) in their blood compared to those without liver dysfunction. The liver function results for both groups are summarized in Table 3.

Table 3 Liver function test results for the children in the two groups.

Severe adenovirus pneumonia with
liver dysfunction (n = 54)
Severe adenovirus pneumonia without
liver dysfunction (n = 276)
P
ALT (IU/L) 175.99 ± 310.09 30.55 ± 16.85 0.000*
AST (IU/L) 215.96 ± 171.34 74.30 ± 58.42 0.000*
Total bilirubin (μM) 16.26 ± 51.02 5.65 ± 2.89 0.049*
Direct bilirubin (μM) 5.52 ± 13.40 2.12 ± 1.23 0.022*
Indirect bilirubin (μM) 10.74 ± 41.83 3.53 ± 2.30 0.227*
LDH (IU/L) 908.43 ± 491.88 755.88 ± 405.62 0.044*

ALT: Alanine aminotransferase; AST: Aspartate transaminase; LDH: Lactate dehydrogenase. *Manne–Whitney U test.Values shown are means ± SD

Lymphocyte subsets analysis

Comparison of circulating lymphocyte subsets between the two liver function groups revealed no significant differences in percentages of total T-lymphocytes, CD4+ T-lymphocytes, CD8+ T-lymphocytes, total B-lymphocytes, or CD4+/CD8+ ratios (Table 4). However, the percentages of natural killer (NK) cells in children with liver dysfunction were significantly lower than in those without liver dysfunction (6.93 ± 4.61 vs 8.71 ± 6.25) (Figure 2).

Table 4 Lymphocyte subsets in children in the two groups.

Severe adenovirus pneumonia
with liver dysfunction (n = 54)
Severe adenovirus pneumonia
without liver dysfunction (n = 276)
P
Total T-lymphocytes (%) 56.87 ± 15.86 54.89 ± 13.89 0.243*
Total B-lymphocyte (%) 36.02 ± 16.69 35.67 ± 14.48 0.728*
CD4+T-lymphocyte (helper; %) 31.88 ± 11.25 31.23 ± 10.61 0.650*
CD8+T-lymphocyte (suppressor; %) 22.93 ± 9.56 21.40 ± 8.24 0.350*
Natural killer (NK) cell (%) 6.93 ± 4.61 8.71 ± 6.25 0.032*
CD4+/CD8+ratio 1.60 ± 0.82 1.66 ± 0.82 0.515*

*Manne–Whitney U test.

Values shown are means ± SD

Figure 2 Percentages of lymphocyte subsets in each group. (A) Total T-lymphocytes; (B) Total B-lymphocytes; (C) CD4+ T-lymphocytes; (D) CD8+ T-lymphocytes; (E) CD4+/CD8+ ratio; (F) NK cells.

Discussion

The human adenovirus is a group of pathogens well known for causing various human illnesses, including upper respiratory tract illness, pneumonia, conjunctivitis, gastroenteritis, and cystitis.9 Adenovirus pneumonia is a common respiratory pathology in children, accounting for 4–10% of all pneumonia cases in children,10 and existing literature suggests that almost one-third of adenoviral pneumonia cases develop into severe pneumonia.11

Besides injuries to the lungs or intestines, the human adenovirus can also lead to liver injury and hepatitis.12,13 This study investigated the clinical characteristics of children diagnosed with severe adenovirus pneumonia with and without liver dysfunction, with the hope of providing important clinical insights about differences in clinical outcomes, liver function tests, and immune cell or lymphocyte subsets between these two groups of patients.

Although our results showed that the median time lag between severe adenovirus pneumonia diagnosis and liver dysfunction was 2 days, with 42 of the 54 children developing this comorbidity within 72 h of pneumonia diagnosis, the underlying mechanism by which adenovirus affects liver functions remains unknown. Whether the liver dysfunction is due to some direct effects from the adenovirus itself or occurs indirectly from an adenovirus-induced amplified inflammatory response or alteration in normal immune function also remains to be clarified.

In this study, lymphocyte subset analyses revealed no significant difference in the percentage of total T-lymphocytes, CD4+ T-lymphocytes, CD8+ T-lymphocytes, total B-lymphocytes, and the ratio of CD4+/CD8+ T-lymphocytes. However, the percentage of NK cells in the peripheral blood of children with severe adenovirus pneumonia complicated with liver dysfunction was significantly lower than those without liver dysfunction (6.93 ± 4.61 vs 8.71 ± 6.25). Although NK cells are innate immune system effector lymphocytes, they can readily limit or exacerbate immune responses.14 In general, NK cells exhibit cytotoxic effects as a result of direct or indirect target recognition. In the direct pathway, identification occurs through signals from NK cells’ surface receptors that receive activating (or inhibiting) signals.15 In the indirect recognition mechanism (antibody-dependent cellular cytotoxicity [ADCC]), the ability of NK cells to express FRIIIa receptors (CD16) permits these cells to target antibody-coated cells.16 A result of this correct target recognition, the killing mechanisms of NK cells are activated, which includes the exocytosis of cytotoxic granules or death receptor–mediated cytotoxicity.15

In addition to successful target recognition, activation of NK cells’ cytotoxicity can also be triggered by other physiological or exogenous factors. Among these, the interleukins (ILs), mostly IL-2, IL-12, IL-15, IL-18, and IL-21, were found to play critical roles in modulating the activity of NK cells.16,17 NK cells can also promote the inflammatory processes in different ways. For instance, during cecum ligation and puncture–induced shock, NK cells from the blood and spleen migrate to the inflamed peritoneal cavity to amplify proinflammatory activities of the local myeloid cell populations.18 NK cells were also reported to promote inflammatory processes during sepsis, possibly via interactions with macrophages,19 organ infiltration, and their own secretion of proinflammatory cytokines.

Our results showed that the percentage of NK cells in the peripheral blood of children with severe adenovirus pneumonia complicated by liver dysfunction was significantly lower than those without liver dysfunction. We hypo-thesized that this could be due to the following mechanism. Severe adenovirus pneumonia can also cause inflammatory responses similar to sepsis, during which NK cells in the peripheral blood may transfer from the blood to the liver, leading to liver dysfunction in children with severe adenovirus pneumonia, and thus lowering the levels of NK cells in the peripheral blood of children with liver dysfunction compared to those without liver dysfunction.

The liver is a unique anatomical and immunological site where antigen-rich blood from the gastrointestinal tract is pressed through a network of sinusoids and scanned by antigen-presenting cells and lymphocytes.20 The lymphocyte population in the liver is selectively enriched in NK cells that play critical roles in first-line immune defenses against invading pathogens, modulation of liver injury, and recruitment of circulating lymphocytes (Racanelli and Rehermann 2006).21 In this study, the levels of NK cells in the peripheral blood were decreased in children with liver dysfunction compared to those without liver dysfunction, indicating that the NK cells in the peripheral blood were enriched by the liver and led to liver dysfunction, consistent with the results of this study. The concerned time lag between severe adenovirus pneumonia diagnosis and liver dysfunction occurred at a median of 2 days (Q1–Q3: 1–4 days). The time that peripheral blood NK cells were enriched by the liver might be at the early stage of severe adenovirus pneumonia.

Study Limitations

This retrospective study had several limitations. Firstly, the adenovirus investigated in this study was not typed. Secondly, the large pooling of data from children not matched for severity of infection or recovery state from the infection likely obscured potential differences between the groups. Thirdly, the interpretation of the results might have also been hampered by the fact that only single blood draws were reviewed, and more representative results could have been obtained with multiple draws over the 28 days postadmission period as this would have allowed the determination of inflection points wherein liver “damage” gave rise to the noted significant differences in NK levels reported above. Lastly, because this was a retrospective study, obtaining vital direct organ (liver)-specific data was difficult, and it would have been impractical to perform liver biopsies and liver ultrasound on these patients outside trial settings. Thus, only indirect measures, such as circulating levels of released hepatic products, were available to compare liver damage across all the study subjects.

Conclusions

A decreased percentage of NK cells in the peripheral blood was found in pediatric patients with severe adenovirus pneumonia complicated with liver dysfunction, indicating that the levels of NK cells in the peripheral blood of pediatric patients with severe adenovirus pneumonia could potentially serve as a marker for monitoring the onset or progression of hepatic damage.

Funding

This work was funded by the Hunan Provincial Science and Technology Department Project (No. 2020SK1014-3, No. 2022JJ40205). The funders had no role in the study design, data collection and analysis, decision to publish, or manuscript preparation.

Ethical Approval

The study protocol was reviewed and approved by the Medical Ethics Committee of Hunan Children’s Hospital (Approval No. HCHLL-2022-59).

Declaration of Interest

The authors declare no conflicts of interest. The authors are responsible for the content of this manuscript.

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