Unusual pediatric lung infections: imaging findings

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a single-stranded RNA virus belonging to the β-coronavirus cluster [15]. The primary mode of transmission for SARS-CoV-2 is through respiratory droplets, which allows rapid spread of the disease. Once the virus is inhaled, it binds to ACE2 receptors on alveolar epithelial cells and leads to cell damage that results in alveolar destruction [16]. This eponymous “unusual (COVID-19) pneumonia” rapidly spread and resulted in a global pandemic, with over 700 million confirmed cases and almost 7 million deaths [17]. The elderly were most severely affected, while children overall demonstrated a milder clinical course with rare cases of severe pneumonia. In children, a post-viral multisystem inflammatory syndrome (MIS-C) was responsible for a more serious clinical course of the disease. This difference may relate to lowered expression of ACE2 receptors in nasal and bronchial tissue in pediatric patients as well as differences in immune system maturity [18].

The clinical presentation and blood laboratory analysis of COVID-19 pneumonia is relatively nonspecific. Cough, fever, myalgia, and fatigue are the most common presenting clinical features. On imaging (Figs. 1 and 2), COVID-19 pneumonia in pediatric patients appears as unilateral or bilateral peripheral (subpleural) and/or posterior, and lower lobe-predominant hazy opacities with or without consolidation [19‐22]. These findings can be detected on chest radiography; however, chest CT is more sensitive for detection and localization of the imaging findings of COVID-19 pneumonia, especially subtle ground-glass opacities which can only be detected on CT [23‐26]. In addition, the CT halo sign is also considered a typical finding of the early phase of pediatric COVID-19 pneumonia [20]. However, the additional CT findings do not affect management in patients with mild to moderate symptoms; therefore, CT is not indicated in these patients and is only typically utilized in patients with a severe COVID-19 pneumonia [25]. Atypical imaging findings, including centrilobular nodules (including tree-in-bud nodularity), cavitation, pleural effusion, and/or lymphadenopathy, are uncommon findings in pediatric COVID-19 pneumonia. Consequently, when present, these atypical imaging features should raise strong consideration for alternative diagnoses [20].

Middle East respiratory syndrome (MERS) is a viral respiratory infection caused by Middle East respiratory syndrome coronavirus (MERS-CoV), also a single-stranded RNA virus belonging to the β-coronavirus cluster [27]. First identified in Saudi Arabia in September 2012, MERS led to a pandemic that spread around 27 countries [28]. MERS-CoV primarily binds to the cell surface protein dipeptidyl peptidase 4 (DDP4), which is abundant in the human respiratory tract. However, DDP4 is also expressed by epithelial cells in the kidneys, small intestines, liver, prostate, and activated leukocytes. MERS-CoV subsequently leads to immune dysregulation, postulated to result in a delayed proinflammatory response in lung epithelial cells [15].

The clinical features of MERS range from asymptomatic or mild disease to acute upper respiratory illness, rapidly progressive respiratory failure with septic shock, multiorgan failure, and death. Although patients of all ages can be affected, the symptoms of MERS are the same across age groups, including fever, dyspnea, and cough [29]. Like COVID-19, children are less commonly affected and typically present with a mild clinical course. Similar to COVID-19, poor outcome is more common in children with concomitant medical comorbidities [30].

Chest radiography is an important imaging modality for both initial evaluation and following disease progression. The most frequently observed chest radiography findings in patients with MERS are unifocal subtle opacities in the middle and basal regions of the lungs, which may eventually progress to multifocal and bilateral airspace opacities as the disease progresses [31]. A fine interstitial reticular pattern of interstitial inflammation has been described in mild disease with progression into diffuse bilateral opacities mixed with air space consolidation in severe illness [5, 30]. On CT, the most frequently observed pattern is ground-glass opacities alone or in combination with consolidation in a peripheral and basilar distribution involving multiple lung segments in more seriously ill patients [32].

Bird flu, also known as avian influenza or avian flu, is a bird disease caused by the influenza A virus. Although influenza A is adapted to birds, it can infect people and sustain person-to-person transmission. It is a single-stranded RNA virus belonging to the orthomyxoviridae family [33]. The most well-known strain is H5N1, which was first isolated from a farmed goose in China in 1996 and caused the first human outbreak in Hong Kong in 1997. Since then, there have been reports of the disease in over 60 countries, primarily in Asia, Africa, the Pacific, Europe, and the Middle East [34]. Unlike COVID-19 and MERS, avian influenza more commonly affects the pediatric population, with almost half of the reported cases being <18 years old [35]. The clinical manifestations of H5N1 infection range from asymptomatic infection to severe pneumonia with multiorgan failure. Fatality rate of hospitalized patients is high, up to 50% [36]. According to the World Health Organization, H5N1 influenza should be considered in all patients presenting with fever, cough, sore throat, shortness of breath, and a positive contact history within 7 days of onset of symptoms with (1) a confirmed human case of H5N1 influenza during the infectious stage; (2) birds that are sick or have died of an unknown illness; (3) a recent visit to an area where there has been an outbreak of H5N1 avian influenza, or to an area where it is now considered endemic; and (4) individuals who have worked in a laboratory that is processing either suspected human or avian samples of the H5N1 infection [37].

The radiographic features of H5N1 pneumonia are reticular opacities with areas of patchy consolidations which rapidly become confluent on follow-up chest radiographs. H5N1 pneumonia is typically multifocal and bilateral, with a predilection for the lower lobes. During the course of the disease, bilateral pleural effusion and cavitations can appear [36‐39]. CT is rarely performed during the acute stage of the disease. On CT, H5N1 pneumonia typically presents as multifocal or diffuse ground-glass opacities with areas of consolidations. CT findings during the convalescent stage can show signs of post-infective fibrosis [37, 38].

Streptococcus anginosus group, previously known as Streptococcus milleri, is a group of three species of streptococci (S. anginosus, S. constellatus, and S. intermedius) that are commensals in the oral cavity and may cause opportunistic severe infections in the abdominal cavity, central nervous system, lung, and pleural space [40]. These pathogens have a striking predilection for abscess formation or empyema that usually require prolonged antibiotic therapy and surgical interventions [41]. While the S. anginosus group is increasingly recognized as a substantial cause of pulmonary infections in adults, especially immunocompromised patients, it is a rare cause of pulmonary infections in both immunocompromised and even immunocompetent children [42, 43].

Affected patients with complicated pulmonary infection present with prolonged fever, respiratory symptoms, chest pain, and chest distress [40]. The most common findings on CT include lung abscesses, found in up to one-third of cases, and consolidations complicated by lung necrosis (Fig. 3). Pleural effusions are common, seen in up to two-thirds of cases. Pleural fluid is usually complex (loculated pleural fluid, with or without septations or split pleura sign), indicative of empyema. Hilar lymphadenopathy is occasionally seen [43]. Although rare, infection with the S. anginosus group should be considered in the differential diagnosis of pediatric patients presenting with empyema or lung abscess, regardless of their immune status.

Tularemia, also known as rabbit fever, is an infectious disease caused by the facultative intracellular gram-negative coccobacillus Francisella tularensis. It is a highly virulent zoonotic disease with sources of human infection in both wild and domestic animals, such as small rodents, rabbits, ticks, and mosquitoes, and in bodies of water. Infection may also occur through the skin, ingestion of undercooked meat, or inhalation of infected aerosols. It does not spread directly between people. Francisella tularensis can be divided into four subspecies: ssp. tularensis, holarctica, mediasiatica, and novicida. Highly virulent subspecies tularensis is found mainly in the USA and Canada, while the less virulent strains are present throughout the Northern Hemisphere [44].

Clinical disease in humans varies according to the mode of acquisition and is described as ulceroglandular/glandular, oropharyngeal, oculoglandular, typhoidal, or pneumonic tularemia. In children, the ulceroglandular/glandular form is the most common by far [45]. Primary pneumonic tularemia is rare. Tularemia pneumonia more commonly develops secondarily through hematogenous dissemination of ulceroglandular or typhoidal disease. Tularemia pneumonia typically presents with fever, general malaise, and respiratory symptoms [46, 47].

Tularemia pneumonia characteristically shows unilateral or bilateral lung consolidative opacities, hilar lymphadenopathy, and pleural effusion on chest radiography (Fig. 4). Chest CT often demonstrates dense lobar lung consolidation, usually in the periphery, and lymphadenopathy [48]. The complications of tularemia pneumonia include lung abscess and acute respiratory distress syndrome (ARDS) [48].

Psittacosis, also known as ornithosis or parrot fever, is an infectious zoonotic disease caused by the obligate intracellular gram-negative bacterium Chlamydia psittaci. Birds are the most common reservoirs of the bacteria and direct contact with infected birds, exposure to their feces, or inhalation of contaminated aerosols may lead to human infection. Person-to-person transmission is rare [49]. Clinical presentation of C. psittaci infection can vary from subclinical or influenza-like symptoms to severe pneumonia complicated with multiple organ dysfunction syndrome. Fever, nonproductive cough, dyspnea, fatigue, headache, and myalgia are the most common symptoms of infection [50, 51]. Psittacosis typically affects bird owners, veterinarians, breeders and sellers of birds, and commercial poultry processors; children are rarely affected [52, 53].

The radiological features of pneumonia caused by C. psittaci are large areas of consolidation or ground-glass opacities, typically bilateral and involving multiple lobes (Fig. 5). Mild to moderate pleural effusion is a common accompanying finding, while mild pericardial effusion is less commonly seen [49]. Neither the radiological features nor the clinical course is specific for diagnosis. Therefore, the potential of a history of contact with birds should be considered in any case of unexplained atypical pneumonia.

Echinococcosis, also known as “hydatid disease,” is a parasitic infection caused by the tapeworm genus Echinococcus [54]. The disease occurs in most areas of the world; however, it is most prevalent in some areas of South America, Africa, and Eurasia [55]. Carnivores (mostly dogs) are the parasite’s definitive hosts and harbor the mature tapeworm in their intestines, while intermediate hosts are usually herbivores such as sheep or cattle. Humans act as accidental hosts who are infected through ingestion of the parasite’s eggs which have contaminated food, water, and soil [54]. Once ingested, the parasite penetrates the intestine to enter the portal system. The liver acts as the first line of defense, and is therefore the organ most commonly affected by this disease (75%); the second most commonly affected organ is the lung (15%).

The disease develops as a slow-growing cystic mass in the affected organ. The initial phase of primary infection is asymptomatic. Many infections are acquired in childhood but do not cause clinical manifestations until adulthood. Pulmonary disease clinically manifests earlier than the disease in the liver; therefore, it is more commonly observed in children [56]. Pulmonary echinococcosis typically presents with chest pain, dry cough, shortness of breath, and hemoptysis, due to the mass effect caused by the cyst. Acute-onset of more severe symptoms, including anaphylactic reaction, may suggest cyst rupture, in some cases patients can expectorate “grape skin”-like material [57, 58].

On chest radiography, an uncomplicated pulmonary hydatid cyst appears as a well-defined homogenous opacity, more commonly appearing in the lower lobes (Fig. 6). There can be multiple cysts in 30% of cases and appear bilaterally in 20% of cases. Calcification in the cyst wall makes the diagnosis almost certain; however, it is rarely seen. Complicated cysts (i.e., eroding a bronchus) can have a more heterogeneous appearance with deformed shape, air inclusions, and air-fluid levels. In such cases, CT can be especially helpful in establishing the diagnosis [57].

Paragonimiasis, also known as lung fluke disease, is a parasitic disease caused by several species of lung flukes belonging to genus Paragonimus, most predominantly P. westermani. The parasite is endemic to Southeast Asia, the Indian subcontinent, South and North America, and Africa [59]. Infection is acquired through consumption of improperly cooked crab, crayfish, or raw meat of wild boar or deer infected with immature forms of lung flukes called metacercariae; tailless, encysted late larvae [60]. After ingestion, the immature forms migrate through the duodenal wall, peritoneal cavity, and diaphragm to become encapsulated and mature within the host, typically in the lungs, or less commonly other organs, including the liver, brain, kidneys, adrenal glands, and lymph nodes.

Common symptoms of paragonimiasis include fever, fatigue, cough, diarrhea, and abdominal pain, while neurological symptoms are far less common. Subcutaneous nodules and hepatomegaly can be recognized during physical examination. Diagnosis is often difficult to establish because of the vague and non-specific symptoms, especially in children who cannot accurately describe their symptoms and dietary history [60].

Chest radiography and CT can be helpful in reaching the diagnosis. Typical chest radiographic findings are pleural effusion, hilar lymphadenopathy, and patchy pulmonary consolidations with ground-glass opacities. On CT, ill-defined pulmonary nodules and consolidation with round low-attenuation cystic lesions filled with fluid or gas can be seen (Fig. 7); intra-cystic worms may be detected [60‐62]. When children from endemic areas present with respiratory symptoms, laboratory findings of eosinophilia, and imaging demonstrations pleural effusion and lung consolidations with internal cystic lesions, diagnosis of paragonimiasis should be strongly considered.

Amoebiasis is caused by the parasitic amoeba Entamoeba histolytica. Amoebiasis is a common parasitic disease in tropical and developing areas, such as Central and South America, Africa, and the Indian Subcontinent, due to lower levels of sanitation, hygiene, and socio-economic status. More recently, with wide-spread global tourism, amoebiasis is becoming a globalized disease [63, 64]. Entamoeba histolytica has two life cycles, one as an infectious trophozoite and the second as a cyst that can survive for months in harsh environments outside the host’s body. The most common route of infection is by ingestion of a mature cyst through contaminated food, water, hands, or sexual contact. Trophozoites release from the cyst in the small intestine and multiply in the lumen of the intestine. Some inhabit the intestinal lumen causing noninvasive infection that enables further spread of the disease, while others invade the intestinal mucosa and cause gastrointestinal disease, or further enter blood vessels and infect extraintestinal organs such as the liver, brain, and lungs [64].

Extraintestinal amoebiasis varies from the most frequent amoebic liver abscess to pulmonary amoebiasis, cardiac infection, or even brain infection. Most extraintestinal amoebiasis begins in the form of an amoebic liver abscess and spreads directly to adjacent organs. Hematogenous spread without hepatic involvement is also possible [65]. Typical symptoms of pulmonary amoebiasis include fever, productive cough, fatigue, and dyspnea. The characteristic imaging feature of pulmonary amoebiasis is abscess formation. When a lung abscess (amoeboma) is formed and connects to the bronchial tree, there is the production of characteristic brown-colored sputum, often clinically referred to as “anchovy sauce sputum” [64].

Chest radiography is the first-line radiologic imaging that can raise suspicion of pulmonary amoebiasis when lung abscess is found. The amoebic abscess is characteristically amorphous in shape, with thick irregular walls, with or without an air-fluid level (Fig. 8). Before the formation of the amoebic abscess, consolidation within the lung and pleural effusion is seen [62]. In a country where amoeba is endemic, the differential diagnosis for thoracic abscess should include amoebic origin, especially in the presence of characteristic imaging features [66].

Hypersensitivity pneumonitis, also previously known as extrinsic allergic alveolitis, is a complicated and heterogeneous interstitial lung disease caused by an excessive immune response to an inhaled antigen in susceptible individuals appearing as inflammation and/or fibrosis of the lung parenchyma and small airways. Hypersensitivity pneumonitis has a predilection for women and older individuals; however, it is the most frequent chronic interstitial lung disease in children [67]. Although more than 200 sensitizing antigens have been identified, bird antigens are by far the most common causative antigens in children [67]. Accurate diagnosis of hypersensitivity pneumonitis is difficult and necessitates a detailed exposure history, as well as a multidisciplinary clinical, histopathologic, and radiologic evaluation.

The diversity of clinical manifestations depends on the nature of the causal agent, the duration of exposure, and host factors. The disease can be classified as acute/inflammatory or chronic/fibrotic form. The acute/inflammatory form is denoted by a disease lasting <6 months and is often reversible. In this form, typical symptoms are dyspnea, cough, and, less commonly, wheezing and weight loss. Chronic/fibrotic form is characterized by a disease lasting >6 months and the presence of fibrotic changes on CT imaging or histology. In this form, typical symptoms are gradual respiratory failure with chronic dry cough and weight loss [68].

Radiological findings of hypersensitivity pneumonitis vary according to the stage of the disease. Although chest radiography can help identify the disease, CT is increasingly used, as it is more sensitive for subtle ground-glass opacities and identification of fibrosis [69]. In the acute/inflammatory form, CT typically shows patchy or diffuse bilateral ground-glass opacities, small centrilobular nodules, lobular areas of reduced attenuation and vascularization (i.e., mosaic attenuation), and air trapping on expiratory images (Fig. 9). Thickening of the interlobular septa, traction bronchiectasis, and a subpleural honeycomb pattern are signs of chronic/fibrotic form. The lung bases are typically spared [70].

Pulmonary hemorrhage is extravasation of blood into airways and/or lung parenchyma. It is an uncommon, potentially life-threatening event that affects children of all ages and can be associated with a wide range of diseases. It characteristically presents with hemoptysis, although some children have a more elusive presentation with cough, tachypnea, dyspnea, wheezing, and even fever [71]. Although pulmonary hemorrhage can be localized or diffuse, the localized form is more common. There are numerous causes for localized pulmonary hemorrhage, such as infection, congenital malformation, vascular anomalies, bleeding diathesis, trauma, and foreign body. Diffuse pulmonary hemorrhage is usually associated with an underlying systemic disease (e.g., vasculitis, idiopathic pulmonary hemosiderosis, coagulopathy, celiac disease, post-bone marrow transplantation, drugs, pulmonary veno-occlusive disease, pulmonary hypertension) [72].

There are no pathognomonic radiographic findings for pulmonary hemorrhage. On radiographs, localized hemorrhage may appear as patchy alveolar opacities or dense consolidation. Diffuse hemorrhage appears as a symmetric diffuse hazy ground-glass pattern, which typically predominates in the lower lung zones with sparing of the apices and costophrenic angles. Diffuse pulmonary hemorrhage secondary to vasculitis may have an asymmetric or patchy distribution [73]. A characteristic feature of hemorrhage is rapid resolution of radiological opacities over 2–3 days, unless hemorrhage is ongoing or repetitive [71]. As hemorrhage clears, an interstitial pattern with thickening of the interlobular septa may emerge. Within a couple of weeks, chest radiographs typically normalize. However, following repeated episodes of pulmonary hemorrhage, a reticulonodular pattern of interstitial fibrosis develops. The CT findings of pulmonary hemorrhage correlate well with chest radiography. CT is a useful adjunct to radiography in the evaluation of localized pulmonary hemorrhage for depiction of the underlying disease and is also a valuable imaging modality for embolization planning in patients with massive hemorrhage (Fig. 10). Findings suggestive of pulmonary vasculitis on CT include fluffy, centrilobular, perivascular densities found centrally and peripherally. Patients with a normal chest radiograph and a high suspicion of pulmonary hemorrhage may benefit from CT for the diagnosis and differentiating it from other potential diagnostic considerations [71].

Eosinophilic pneumonias are a large group of interstitial lung diseases characterized by a substantial infiltration of the alveolar spaces and lung interstitium by eosinophils, with conservation of the lung structure. Idiopathic eosinophilic pneumonias are rare entities and pediatric case descriptions are scarce. Diagnosis of eosinophilic pneumonia relies on the demonstration of alveolar eosinophilia on bronchoalveolar lavage and elimination of a secondary cause (parasitic or fungal infection, asthma, cystic fibrosis, drug effect). Idiopathic eosinophilic pneumonias can have acute and chronic presentations. Acute eosinophilic pneumonia clinically presents as a hypoxic and febrile acute respiratory distress syndrome, accompanied by myalgia. Chronic eosinophilic pneumonia has a slower progressive clinical presentation beginning with prolonged dry cough [74].

The radiographic pattern of acute eosinophilic pneumonia is nonspecific. Diffuse interstitial and air-space opacities without peripheral predominance, interlobular septal thickening, and pleural effusions can be observed. The random distribution of abnormalities and pleural effusion are important diagnostic features [75]. The radiographic pattern in the chronic form is more specific with non-segmental peripheral airspace consolidation (i.e., reverse batwing appearance) involving mainly the middle and upper lobes. In the later stages of eosinophilic pneumonia, ground-glass opacities, pulmonary nodules, and reticulation can be demonstrated on chest CT (Fig. 11). Pleural effusion is not a common finding [76].