Adenovirus in Paediatric Population PDF

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b i o m e d i c a l j o u r n a l 4 5 ( 2 0 2 2 ) 3 8 e4 9 Available online at www.sciencedirect.com ScienceDirect Biomedical Journal journal homepage: www.elsevier.com/locate/bj Review Article: Special Edition Human adenovirus infections in pediatric population - An update on clinicoepathologic correlation Wun-Ju Shieh* Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan article info abstract Article history: Human adenoviruses can cause infections at any age but most commonly in pediatric Received 8 July 2021 population, especially in young children and infants. By the time of 10 years old, most Accepted 30 August 2021 children have had at least one episode of adenovirus infection. Adenoviruses can cause Available online 10 September 2021 many symptoms similar to common cold, including rhinorrhea, fever, cough, and sore throat. Lower respiratory infections such as bronchitis, bronchiolitis, and pneumonia can Keywords: be severe and even fatal. Other diseases such as conjunctivitis, gastroenteritis, cystitis, Human adenoviruses myocarditis, cardiomyopathy, and meningoencephalitis can also be associated with Pediatric infections adenovirus infections. A variety of recent advancement of structural and molecular biology Epidemiology methods have revamped the taxonomy of adenoviruses and furthered our understanding Clinicoepathologic correlation of the diversity of related clinical diseases. Because of the wide spectrum and complexity of diseases associated with human adenovirus infections, the scope of this review is limited to basic virology and epidemiology of adenoviruses with a main focus on the clinico epathologic correlation. Clinical manifestations and pathology of any infectious disease are always related; therefore, it is logical to review clinicoepathologic correlation within the specific disease entity caused by adenoviruses to better understand this common viral infection in pediatric population. medium-sized (70e100 nm), nonenveloped viruses with an Virology icosahedral nucleocapsid containing a double-stranded linear DNA genome 34e36 kbp length [Fig. 1A]. The icosahedral shell Human adenoviruses (HAdVs) are members of the Adenovir- is composed primarily of 240 capsomeres of hexon trimers, 12 idae family. The name derives from the initial isolation of the pentameric penton capsomeres at each vertex of the icosa- virus from human adenoids in 1953. Adenoviruses are hedron, and 12 fibers extending from the pentons [Fig. 1B]. The * Corresponding author. Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical Uni- versity, 250 Wu-Hsing St., Taipei 11031, Taiwan. E-mail addresses: [email protected], [email protected]. Peer review under responsibility of Chang Gung University. https://doi.org/10.1016/j.bj.2021.08.009 2319-4170/© 2021 Chang Gung University. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).  b i o m e d i c a l j o u r n a l 4 5 ( 2 0 2 2 ) 3 8 e4 9 39 Fig. 1 (A) Transmission electron micrograph with an ultra-thin section of an adenovirus-infected cell showing adenoviruses replicate in the nucleus of cells and form intranuclear paracrystalline arrays of 70e90 nm adenovirus particles. (B) Structure of adenovirus virion. Non-enveloped capsid with an icosahedral symmetry and nucleocapsid containing a double-stranded linear DNA genome. The icosahedral shell is composed of 240 capsomeres of hexon trimers (12 per triangular facet of the icosahedron), 12 pentameric penton capsomeres at each vertex, and 12 fibers extending from the pentons. hexon has been established to carry the antigen specificity of the fiber knob domain to the host-cell transmembrane CAR markers a and ε with group, subgroup and type-specific protein (coxsackie B, adenovirus receptor), which is abun- immunogenicity and neutralization. The penton base dantly expressed in a variety of tissues. In contrast to carries b epitope and reacts as a minor group-specific antigen. other HAdV species, fiber knobs in the B species and species D It has been associated with cellular toxicity and interacts with Ad37 bind CD46, a regulator of the complement cascade pre- the inner surface of endosomes during disruption of inter- sent on the plasma membrane of most cell types, including nalized vesicles. The fiber contains a major antigen, g, and hematopoietic cells [11,12]. is responsible for type specificity, cell attachment, and hem- HAdV species C is known for its ability to establish agglutination. Because of their important roles in cell entry persistence and latent infections in lymphoid organs such as and establishment of host infection, these structural proteins tonsils and adenoids. Ad5 is a member in species C and are crucial in the pathogenesis of HAdV infections. HAdVs has been widely used as a recombinant, non-replicative vector bind to cell surface receptors and trigger internalization by for vaccine development [14,15], including the recent COVID- endocytosis. Viral messenger RNA transcription, genomic 19 vaccine formulations [16,17]. Adenoviruses are considered replication, and progeny virion particles assemble all occur in excellent vectors for vaccine development or cancer therapy the nucleus. The infected cells will subsequently lyse and because they can deliver target antigens to mammalian hosts release viral particles. The replication process and cellular efficiently with the following properties: 1) They contain a lysis of HAdV infection produce unique cytopathologic fea- relatively large-sized and well-defined genome for genetic tures, which will be described later. manipulation; 2) The risk of insertion mutagenesis is much Advances in structural biology methods (such as cryo- less than other viral vectors, such as retrovirus, because ad- electron microscopy), availability of novel techniques (such enoviruses do not integrate the viral genome within the host as atomic force microscopy), and discovery of new viruses genome; 3) They can grow to high titers with higher thermo- have resulted in notable advances in our understanding of the stability, and can be easily applied through systemic or res- adenovirus particle organization and its variations piratory routes; 4) They are capable of infecting a wide range throughout the different species and genera [6,7]. Currently, of cells due to their broad tissue and cellular tropism; 5) They there are 104 different HAdV types known, which have been induce strong and sustained innate and adaptive immune classified into seven species A to G based on the percentage of responses, including both CD4þ T cell and CD8þ T cell- guanine plus cytosine in their DNA and other biochemical and mediated immune responses; 6) Certain types, such as Ad5, biophysical criteria [Table 1]. Types were exclusively cause asymptomatic or mild infections in humans and their defined as serotypes up to Ad51. A genotype definition was replication can be inhibited by genetic modifications. mostly used for newer types, which requires either novel se- AdV-based vaccines are generally safe with very few quences or recombinant phylogeny in genes coding for major adverse effects. However, there are still possible side effects capsid proteins. The majority of HAdV types belong to associated with AdV-based vaccines. For example, the capa- species D (73 types) followed by species B (16 types), and new bility of Ad5 vectors to sequester platelets has been previously adenovirus types continue to emerge. demonstrated, which can cause temporary thrombocytopenia HAdVs use distinct cellular receptors for attachment and. Recombinant Ad5 can activate platelets via binding the internalization. Initial attachment of HAdVs in species A, C, D, platelets CD62 and increases D-dimer for at least 6 h following E, and F (but not species B) is mediated by high-affinity binding Ad5 introduction. Despite such evidence, the rate of 40 b i o m e d i c a l j o u r n a l 4 5 ( 2 0 2 2 ) 3 8 e4 9 Table 1 Human adenovirus classification, associated clinical diseases, epidemiologic features, seroprevalence and distribution. Species Types Clinical Diseases Epidemiologic Seroprevalence and Distributiona Features A 12, 18, 31, 61 Gastroenteritis Rare cause of Ad31: 73% in Belgium gastroenteritis in children B 3, 7, 11, 14, 16, 21, 34, 35, *Conjunctivitis *Outbreaks of Ad3: 90e100% in the USA; 69% in Belgium; 50, 55, 66, 68, 76-79 xAcute respiratory conjunctivitis due to 18% in Germany; 80% in Southern China; diseases inadequate chlorination 40e73% in Singapore; 42e62% in Japan Common cold of swimming pools; Ad7: 26e78% in the USA; 38% in Belgium; Bronchitis transmission via 13e86% in China; 3e13% in Japan; 7e31% Bronchiolitis swimming or in Singapore Pneumonia swallowing water Ad11: 3e18% in the USA; 6e22% in Europe; yHemorrhagic cystitis xThird most common 16e40% in Sub-Saharan Africa; 18e30% in yMeningoencephalitis cause of viral respiratory Japan yMyocarditis infection in children Ad14: 25% in China; 51e56% in North and yGastroenteritis under the age of 4 years; South America; 17% in Belgium transmitted via aerosols Ad35: 7e22% in the USA; 39  C). On physical examination, moderate to severe dys- showed HAdV species B, C, and E were detectable in adenoid pnea with associated tachypnea is apparent. Auscultation and palatine tonsil tissues and nasopharyngeal secretions reveals inspiratory and expiratory wheezes and rales. Chest from nearly 85% of children with adenotonsillar hyperplasia radiographs usually demonstrate bilateral diffuse infiltrates, or recurrent tonsillitis. There is no association with the which may be bronchial, peribronchial, or interstitial [61,62]. severity of airway obstruction, nor with the presence of Pleural effusion or mediastinal lymphadenopathy has rarely recurrent tonsillitis, sleep apnea or otitis media. The histo- been described. Other clinical manifestations include leth- pathology shows follicular hyperplasia with increased lym- argy, sore throat, diarrhea, anorexia, vomiting, and occa- phocytes and macrophages. No characteristic viral inclusions sionally conjunctivitis. Extrapulmonary complications that are observed. Epithelial and subepithelial cells in tonsils seem have been reported include meningitis, encephalitis, hepati- to be crucial for HAdV species C production and shedding in tis, myocarditis, nephritis, disseminated intravascular coa- such persistent HAdV infection. gulopathy, and skin rashes [55,59,63e65]. However, many of these disease entities are observed based on clinical mani- Acute bronchitis and bronchiolitis festations or laboratory tests without histopathologic corre- HAdVs account for approximately 5%e11% of bronchitis lation. In surviving infants, symptoms may persist for 2e4 and 5%e18% of bronchiolitis in infants. The bronchiolitis weeks, and radiographic changes resolve slowly at the 3-week caused by HAdVs is usually sporadic and similar to illness follow-up examination. Recovery often is gradual, and exac- associated with other viral agents. Many cases of bronchiolitis erbations occur commonly. eventually progress to pneumonia. Adenoviral bronchiolitis The histopathologic findings in fatal cases of adenoviral that occurs early in infancy can be fatal or results in serious pneumonia usually show necrotizing bronchitis and bron- residual lung damage and chronic disease. chiolitis with extensive denudation of the surface epithe- lium, particularly in medium-sized intrapulmonary bronchi. Bronchiolitis obliterans The lamina propria of bronchi and bronchioles is typically Bronchiolitis obliterans (BO) is an uncommon and severe congested, edematous, and infiltrated with predominantly sequela of chronic obstructive lung disease in children that mononuclear inflammatory cells [Fig. 3E]. Amorphous results from a damage to the lower respiratory tract. It typi- eosinophilic material, mixed inflammatory cells, sloughed cally occurs after a severe respiratory infection in previously epithelium, and cellular debris may occlude affected air- healthy pre-school children. HAdV infection may be a major ways. Serous and mucous glands in bronchi are often cause of post-infectious bronchiectasis and BO in childhood involved with necrotizing inflammation as well. The pul- [52,53]. Children with severe adenoviral pneumonia who have monary parenchyma usually shows bronchocentric necrosis a longer duration of fever (especially more than 10.5 days), with hemorrhage, mixed inflammatory infiltrates, and develop dyspnea, or require invasive mechanical ventilation abundant karyorrhectic debris [Fig. 3G]. These findings in the acute phase are more likely to develop BO. Symp- generally occur on a background of exudative diffuse alve- toms and signs of air trapping, such as hyperinflated chest or olar damage (DAD), which shows macrophages, fibrin, and expiratory wheeze with persistent oxygen requirement are detached pneumocytes in alveoli. Hyaline membrane for- characteristic findings in BO. The histopathologic features mation may be observed at early stage of DAD. Disseminated usually show necrotizing inflammation in bronchi, bronchi- intravascular coagulopathy and fibrin thrombi in vessels oles, alveoli, bronchial mucous glands, with the presence of may be present in lung and other organs, such as kidney, intranuclear inclusions. heart, adrenals, and central nervous system. Typical intra- nuclear inclusions can be seen in respiratory epithelial cells Pneumonia of the trachea, bronchi, and bronchioles, as well as in the HAdVs are common isolates in young children with pneu- acinar cells of bronchial glands and in alveolar pneumocytes monia. The overall frequency of HAdVs as a cause of [Fig. 3G]. They are usually more abundant around the nonbacterial pneumonia in children is less than that of res- necrotic foci. On routine hematoxylin and eosin stain, early piratory syncytial virus and parainfluenza virus type 3, but an inclusions appear as “Cowdry type A inclusions” with small, alarming number of fatal illnesses have been reported. dense, amphophilic structures surrounded by a clear zone Adenoviral pneumonia is probably responsible for about 10% and peripherally marginated chromatin. Unlike herpetic or of the pneumonias of childhood and can occur in epidemic or paramyxoviral infections, no multinucleated giant cells or sporadic pattern [55,56]. Ad3, 7, and 21 are the most common syncytial cells are seen. As the infection progresses, the etiologic types of adenoviral pneumonia between 6 months characteristic “smudge cells” become more apparent and and 5 years of age [55,57]. Ad3 and Ad7 are particularly path- abundant with larger and more basophilic inclusions, and ogenic types that can disseminate and often cause fatal dis- the margins of the nuclear membrane become less distinct ease in previously healthy children. Periodic epidemics of [Fig. 3G]. This is due to the inefficient assembly of viral par- adenoviral pneumonia in young adults have also been iden- ticles and accumulation of large number of nucleic acids and tified, particularly Ad4 among military recruits. peptides in the infected cells, as previously described. The  b i o m e d i c a l j o u r n a l 4 5 ( 2 0 2 2 ) 3 8 e4 9 45 presence of HAdV inclusions can be highlighted by using IHC gastroenteritis in children [77,78]. The incidence of adenoviral with specific antibodies [Fig. 3F and H]. The pathologic fea- gastroenteritis differs considerably in various studies and tures of necrotizing inflammation in bronchi, bronchioles, geographic locations reported by many authors. In general, and lung parenchyma correlate well with the clinical mani- HAdV infections are the cause of 2%e15% of acute diarrheal festations of bronchitis, bronchiolitis, and pneumonia. illnesses in children. It is less prevalent than rotavirus infec- tion, occurs most often in children younger than 4 years of Heart age, and is not easily distinguishable from other infectious gastroenteritis based on clinical manifestations. Outbreaks Myocarditis associated with Ad3 and Ad7 infections have been reported Enterovirus infections, such as coxsackieviruses have been with acute abdominal pain followed by diarrhea, nausea and considered as the most common etiologic pathogens of viral vomiting, fever, headache, and pharyngitis [79,80]. Other myocarditis in pediatric population. However, there is evi- symptoms that may occur in patients with adenoviral diar- dence that HAdVs may be a significant cause as well [67,68]. rhea include conjunctivitis, rhinitis, pharyngotonsillitis, and Such evidence mainly comes from utilization of PCR assays to cervical adenitis. Adenoviral gastroenteritis is usually self- detect the presence of nucleic acids in clinical samples. In an limiting and lasts approximately 2e3 days. Microscopic find- extensive study of myocarditis, HAdV DNA was identified by ings in biopsy samples from patients with adenoviral diarrhea PCR in 23% of the endomyocardial biopsy. The results shows non-specific inflammation and infected epithelial cells suggest that HAdVs may play an important role in viral with characteristic nuclear and cellular changes. myocarditis. In children, myocarditis has been noted in as- sociation with severe pneumonia and disseminated disease Intussusception caused by several types of HAdVs [68,69]. However, the etio- HAdV infections have been well documented to be associated logic role of HAdVs in myocarditis remains controversial. Viral with intussusception [82,83]. Previous studies have suggested particles have not been observed by EM and the characteristic that bowel wall hypermotility caused by direct viral involve- cytopathic features, such as smudge cells or intranuclear in- ment or by hyperplasia of lymphatic tissue is the lead point for clusions are usually not observed in tissue samples of the intussusception. Many HAdV types have been implicated myocarditis cases. and species C represent the largest proportion in identification. Most children with intussusception were younger than 2 Dilated cardiomyopathy years old and some had preceding respiratory symptoms. In Dilated cardiomyopathy (DCM) is the most common type of these cases, viral inclusions can be seen in surface or nonischemic cardiomyopathy, and most cases of DCM are desquamated gastrointestinal epithelium [Fig. 3I] and can be idiopathic. Recently, the human coxsackievirus and adeno- confirmed by using IHC assay [Fig. 3J]. Mesenteric lymph virus receptor (CAR) was discovered, and its increased nodes often are enlarged at surgery. The lymphoid follicles expression has been reported in patients with DCM and adjacent to the intussusception areas are usually hyperplastic myocarditis [70,71]. A previous study showed 12% had HAdV [Fig. 3K] and viral antigens can be demonstrated by IHC DNA demonstrated by PCR in the endomyocardial biopsy staining [Fig. 3L]. Typical adenoviral intranuclear inclusions specimen from patients with DCM. A more recent study can also be demonstrated in cells in stool, intestinal epithe- shows that myocardial infection with HAdV may play an lium, and the appendix by electron microscopy. important role in the pathogenesis of severe DCM. Further studies are needed to elucidate the pathogenesis of DCM Appendicitis and mesenteric lymphadenitis caused by HAdV infection. HAdVs have been reported in both acute and chronic appen- dicitis. Right iliac fossa abdominal pain in conjunction Pericarditis with sore throat is a common finding. The virus has been Pericarditis associated with severe adenoviral pneumonia has isolated from the appendix and mesenteric lymph nodes at been reported [73,74], albeit rare. A report described a 10- surgery. During acute infection, evidence of HAdVs can be month-old boy with fatal pericarditis caused by Ad7. discerned with characteristic intranuclear inclusions and Interleukin-6, tumor necrosis factor-a, and adenovirus- positive IHC staining in lymphoid follicles of the ileum, ap- specific immune complexes were identified in serum and pendix, and mesenteric lymph nodes. In chronic infection, pericardial fluid from this child. In another report, elec- only mild non-specific inflammation is seen in the appendix. trocardiographic changes were consistent with pericarditis in Several types of HAdVs have been recovered from lymph a child with Ad7 pneumonia and the virus was isolated in high nodes and the appendix in cases of mesenteric lymphadenitis titer from pericardial fluid at postmortem examination. [82,87]. Patients with mesenteric lymphadenitis often have abdominal pain and other symptoms similar to those of acute Gastrointestinal tract appendicitis. Mesenteric adenitis may be associated with concurrent or recent adenoviral illness, such as pharyngitis. Gastroenteritis The widespread use of electron microscopy for the study of Hepatitis rotaviral diarrhea led to the finding of previously unrecog- Hepatitis in association with HAdV infection has been re- nized HAdVs that were fastidious and could not be grown in ported in small infants, mainly in children with overwhelming routine cell cultures. These HAdVs, now identified as Ad40 disseminated disease or in immunocompromised patients and Ad41, subsequently were shown to be important causes of [88,89]. Few cases of HAdV hepatitis in immunocompetent 46 b i o m e d i c a l j o u r n a l 4 5 ( 2 0 2 2 ) 3 8 e4 9 pediatric patients have been documented. Adenoviral hepa- Immunocompromised patients are also susceptible to a titis can occur secondary to hepatic transplants or by the broader range of different HAdV infections. HAdV infection spread of virus to the liver hematogenously in sporadic cases. has been a common complication in bone marrow/hemato- In transplants, it may be directly related to infection of the poietic stem cell transplant and solid organ transplant re- transplanted liver or reactivation of the virus from a latent cipients [96,97]. Because some HAdVs establish latency in source. Focal inflammatory infiltrates with hepatocellular lymphoid tissues and the kidneys of their host, it is believed necrosis and typical smudgy cells can been seen [Fig. 3M]. that many cases of clinical disease caused by HAdVs in Pathologic diagnosis can be confirmed by PCR, IHC [Fig. 3N], immunocompromised patients are actually reactivated in- and thin section transmission EM. fections. A rare but fulminant form of adenovirus-associated Genitourinary tract hemophagocytic lymphohistiocytosis (HLH) has been re- ported in children. Most of these HLH cases were associated Acute hemorrhagic cystitis with severe HAdV pneumonia or bone marrow transplant Acute hemorrhagic cystitis is an uncommon manifestation of recipients [99,100]. Bone marrow aspiration or lymph node HAdV infection in immunocompetent children and is char- biopsy from HLH patients typically reveals increased numbers acterized by a sudden onset of dysuria and frequency, with of histiocytes with hemophagocytosis [Fig. 3P]. The evidence hematuria developing 12e24 h later [90,91]. It occurs more of HAdV infection in such cases is usually confirmed by frequently in boys and usually is associated with Ad11. Oc- serology or PCR assays. casionally, fever, suprapubic pain, and enuresis may occur. Symptoms can persist for a few days to 2 weeks, with average duration being approximately 5 days. HAdV antigen has been Conclusions identified by immunofluorescence in exfoliated bladder cells. Although no sequelae have been reported, the long-term The tissue tropism, cytologic features, and histopathologic prognosis is unknown. changes of HAdV infections correlate well with the biologic properties of the virus. The clinical manifestations correspond Nephritis to the organ systems involved in HAdV infection and the de- Hematuria occasionally has been reported in infants with gree of tissue damage with host immune responses. There is severe pneumonia and disseminated HAdV infection. Some still a need to conduct further studies to elucidate the patho- children with upper respiratory illnesses caused by HAdV, genesis of this common viral infection in pediatric population. specifically in patients with PCF have also been noted to manifest with hematuria. A series of autopsy cases of necrotizing tubulointerstitial nephritis caused by HAdV Conflicts of interest infection showed hemorrhagic, necrotizing tubulitis with intranuclear inclusion bodies in the kidney. The presence The author declares no conflicts of interest. Some of the work of hemorrhagic cystitis and localization of invasive infection described in this manuscript was done when the author was in urogenital organs suggested that renal infection might working as a medical officer at Infectious Diseases Pathology occur by ascending route from the bladder. Histopathologi- Branch, Centers for Disease Control and Prevention, Atlanta, cally, typical smudge cells or Cowdry type A intranuclear in- Georgia, USA. clusions are present in necrotic tubular epithelial cells surrounded by inflammatory cells [Fig. 3O]. Immunofluores- cent or IHC examination with anti-HAdV antibody can Acknowledgement demonstrate viral antigens in the affected tubular cells. 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