Case report: refractory atelectasis after infection of adenovirus and Mycoplasma Pneumoniae in an immunocompetent patient

Abstract

Background

Atelectasis is defined as collapse of alveolar spaces due to a variety of reasons. Most atelectasis could improve after removing the cause by chest physiotherapy, medical treatment, therapeutic bronchoscopy and so on. However, some atelectasis cannot be cleared with above treatments, resulting in long-term atelectasis, also called as refractory atelectasis. It easily leads to recurrent infection, bronchiectasis, bronchiolitis obliterans, and lung necrosis. So, it is important to identify causal mechanism of refractory atelectasis, which may contribute to explore effective approach and reducing complications.

Case presentation

We present the case of a 4-years-old girl admitted to hospital with fever and cough for 6 days, who had pulmonary consolidation in left lower lobe due to human adenovirus-7 and Mycoplasma pneumoniae. Although the patient did not have inborn errors of immunity, neuromuscular disease or inherited metabolic diseases through medical history and laboratory examination, the consolidation of the left lower lung still existed after a series of treatments, including mechanical ventilation, intravenous immunoglobulin, systemic corticosteroid, azithromycin and bronchoalveolar lavage. Even, chest HRCT showed left lung atelectasis one month after discharge. In the follow-up 1 years, she was hospitalized for respiratory infections and wheezing 4 times. In consideration of refractory atelectasis and recurrent infections, left lung was resected by thoracoscopy and postoperative pathology confirmed bronchiolitis obliterans. Specific antibodies was utilized to identify type I and II alveolar epithelial cells, club cells, ionocytes and ciliated cells respectively, which show a selective reduction in type I alveolar epithelial cells.

Conclusion

It is rare that a previously healthy child developed to refractory atelectasis after an infection which ultimately resulted in a lobectomy. The cellular analysis of the atrophic lung tissue showed a selective reduction in type I alveolar epithelial cells.

Background

Atelectasis is a condition characterized by the reduction of volume or air content of one or more lung tissues due to a variety of reasons, resulting in functional tissue collapse or atrophy, alveolar hypoxia, pulmonary vasoconstriction and improper ventilation-perfusion matching [1]. Atelectasis can occur through various mechanisms, including airway obstruction (such as mucous plug, plastic bronchitis), compression by extrathoracic or intrathoracic factors, and alterations in surface tension within the alveoli [2]. The most common cause of atelectasis is infection [3]. Descriptive categorization of atelectasis includes subsegmental, segmental, lobar, or whole lung involvement [4].Most atelectasis can be cleared after removing the cause of disease, anti-infection, bronchoalveolar lavage (BAL), physical therapy and so on, but some atelectasis cannot through above treatments, described as refractory atelectasis, also meant long-term atelectasis [3, 5]. At present, there are few studies on refractory atelectasis or long-term atelectasis, and most of the refractory atelectasis reported in children were cystic fibrosis, bronchiectasis, immunodeficiency and complicated with neuromuscular diseases [2, 6, 7]. It is unusual for a previously healthy and immunocompetent child to present with refractory atelectasis.

Human adenovirus (HAdV) and Mycoplasma Pneumoniae (MP) both are important pathogens of community-acquired pneumonia (CAP) in children, both of them are the common pathogenes leading to atelectasis [8, 9]. Children sometimes get co-infected with both HAdV and MP. As we all know, HAdV infection to be a remarkably strong post-infectious bronchiolitis obliterans (PIBO) -associated etiological agent in children [10]. The common imaging findings of PIBO are Mosaic sign, while long-term atelectasis is rare. Currently, there is a lack of study suggested an association between infection of HAdV or MP and refractory atelectasis. In our case, a previously healthy child developed long-term atelectasis of her left lung needing lobectomy after HAdV and MP infection. What puzzled us was why our patient present with refractory atelectasis.

Case presentation

A previously healthy 4-years-old girl was admitted to hospital because of fever and cough for 6 days. The patient denied any history of recurrent infection, recurrent wheezing, allergies or special pathogens infectious such as tuberculosis, and had no family history of allergies, asthma or immune deficiency.

During hospitalization in local children's hospital, the patient rapidly developed to respiratory failure needing trachea intubation and mechanical ventilation. Empirical treatment with β-lactam/β-lactamase inhibitor combinations (BLICs) were given owing to the elevation of C-reactive protein (CRP). Bronchoscopy combined with BAL were performed because of lung consolidation in left lower lobar found by high-resolution computed tomography (HRCT) of chest. Due to a positive result of HAdV- 7 and MP through the next generation sequencing (NGS) of bronchoalveolar lavage fluid (BALF), azithromycin, intravenous immunoglobulin and systemic corticosteroid were also given. Despite above aggressive treatment, the patient worsened with recurrent hyperpyrexia, depend on mechanical ventilation and even progressive decline in white blood cells (WBC). After 1 week of hospitalization, the patient was transferred to our hospital.

On examination when the patient transfered to our hospital, breath sounds were low in the left lower lung, moderate moist rales were heard in both lungs and a few marbled skin discoloration were visible but without erythra and haemorrhage dot. The liver and spleen was not palpable subcostal.

On laboratory examination, the count of WBC was lower (2.0 * 10^9/L) and the level of CRP was higher (165 mg/L). Serum ferritin was over 500 ng/mL (1469.20 ng/ml), but the fibrinogen and triglyceride were normal. Other laboratory test results are shown in Table 1. In addition, the immunity function of this patient was also measured, with a normal result in the humoral immunity. As for cellular immunity, the count of T-cell and NK-cell were decreased, but normal on subsequent retest (see Table 1).

Table 1.

Laboratory data at admission and before discharge when the patien first time admitted

Indexs	At Admission	Before Discharge	Reference range
Blood routine examination
White-cell count (WBC) (* 10^9/L)	2.0	5.5	5–12
Neutrophils (NE) (* 10^9/L)	1.62	2.33	2–7.2
C-reactive protein (CRP) (mg/L)	165	5	0–6
Serum biochemical indices
Alanine aminotransferase (ALT) (U/L)	80	43	7–40
Aspartate aminotransferase (AST) (U/L)	118	70	5–60
Albumin (ALB) (g/L)	31.2	45.7	40–55
Lactate dehydrogenase(LDH) (U/L)	1055	201	159–322
Triglyceride (TG) (mmol/L)	1.59	-	0.23–1.70
Ferritin (ng/mL)	1469.2	126	10–291
Coagulation function tests
Prothrombin time (PT) (S)	13.1	12.3	11–15
Activated partial thromboplastin time (APTT) (s)	42.4	40.2	28–45
Fibrinogen (FIB) (g/L)	5.14	2.01	2–4
Immunity function tests
Immunoglobulin G (IgG) (g/L)	17.7	9.66	5–10.6
Immunoglobulin A (IgA) (g/L)	1.34	0.72	0.34–1.38
Immunoglobulin M (IgM) (g/L)	2.43	0.7	0.44–1.44
Immunoglobulin E (IgE) (IU/mL)	98	39	0–60
T-cell counts (cell/ul)	211.33	1612.9	690–2540
CD4+ T-cell counts (cell/ul)	135.02	893.88	410–1590
CD8+ T-cell counts (cell/ul)	54.50	716	190–1140
B-cell counts (cell/ul)	141.90	316.69	90–660
NK-cell counts (cell/ul)	36.46	331.57	90–590

After admission, mechanical ventilation and two course of azithromycin were continued. Considering the serious condition, progressive increase in CRP and decrease in WBC, empirical therapy with meropenem was given. The temperature of the patient become normal on the 2nd day, the count of WBC and the level of CRP become normal on the 5 th day after admission. Successful weaning from the ventilation on the 11 th day. Recheck cellular immunity became normal (see Table 1). Reexamination of HRCT revealed the lung consolidation was still in left lower lobar (see Fig. 1A) and bronchoscopy combined with BAL was operated again, which result suggested bilateral airways with normal morphology, without bronchial obstruction or obliteration. The patient was discharged due to improvement of symptoms and the length of stay was 20 days.

Fig. 1.

HRCT Scans of the Chest. A HRCT of chest before discharge revealing that uneven inflation of both lungs, large sheets of high-density shadow in the left lower lobe and occlusion of partial distal bronchus branch in the left lower lobe. B HRCT of chest 1 month after discharge revealing atelectasis of the left lung, compressed near the lung portal, compensatory enlargement of the right lung, hyperinflating and protruding to the left thoracic cavity, and displacement of the mediastinum to the left. C HRCT of chest 2 months after left pneumonectomy revealing compensatory enlargement of the right lung and compensatory enlargement of the right lung

Inhaled corticosteroid and oral low dose azithromycin (5 mg/kg/d, 3 days a week) were maintained after discharged, while after 1 month chest HRCT showed atelectasis of the left lung yet, with hyper-inflating of the right lung and mediastina shift to left (see Fig. 1B). Also, whole-exome sequencing was carried out and found a missense mutation in the MUC5B gene (c.15064 C > G), resulted in substitution of an Leu residue by Val at codon 5022 (p.Leu5022 Val), whether the mutation show meaningful is indeterminate. In the follow-up 1 year, this patient needed hospital for 4 times due to fever and/or cough or wheeze. Repeated chest CT scans revealed atelectasis in the left lung, progressive compensatory volume enlargement of the right lung and mediastinal hernia. Pulmonary function examination indicated mild obstruction and restricted ventilation disorder (FEV1: 1.01L, FVC: 1.34L, FEV1/FVC: 76%). Due to recurrent respiratory infections, bronchial mucosal biopsy for transmission electron microscopy (TEM) to detect ultrastructural defects in cilia was performed, without the typical ultrastructural pathological changes of primary ciliary dyskinesia (see Fig. 2).

Fig. 2.

Bronchial mucosal biopsy for transmission electron microscopy. The typical ultrastructural pathological changes of primary ciliary dyskinesia was not observed

After 1 year of repeated hospitalization, the patient's guardian chose our hospital again for further examination and treatment. Physical examination revealed that the left lung breathing sounds were still diminished. In consideration of refractory atelectasis in left lung and recurrent respiratory tract infection which seriously affected the quality of life of patients and increased the economic burden, thoracoscopic resection of the left lung was performed after multidisciplinary consultation with consent of the patient's parents. Postoperative pathological results revealed bronchiolitis obliterans (BO)(see Fig. 3).

Fig. 3.

Pathology of left lung. More lymphocyte infiltration around the small airway bronchus, part of small bronchi were occluded, and the fibrosis around the bronchioles was not obvious. Haematoxylin and eosin; magnification × 40

Different from a typical manifestation of BO, persistent atelectasis not"mosaic sign"manifested in the imaging findings of the patient. So, we tried to find whether existed other potentially unknown causes or not by immunohistochemical method. We used antibody AQP5 to mark type I alveolar epithelial cells, SFTPB to mark type II alveolar epithelial cells, CK5 to mark basal cell, CC10 to mark club cell, CFTR to mark ionocyte and FOXJ1/ACCTUB to mark ciliated cell. The results showed that only type I alveolar epithelial cells were decreased compared with normal lung tissue, and the other cells were similar (see Fig. 4A). To verify this result, we also stained the tissue with antibody CK (AE3) and TTF1, which obtain the same result (see Fig. 4B and 4 C).

Fig. 4.

Left lung pathology with Immunohistochemical method. Type 1 alveolar epithelial cells decreased selectively in our patient. Type 1 alveolar epithelial cells stained positive for antibody AQP5 by immunohistochemistry (A), antibody TTF1 (B) and antibody CK(AE3) (C). Magnification × 40

Chest HRCT of the patient was reexamined 2 months after left pneumonectomy as shown in Fig. 1 C. She is still being followed up.

Discussion and conclusion

Although atelectasis is common in children, its persistence or refractoriness to treatment should lead prompt evaluation to identify causal mechanism [11]. In our case, an immunocompetent patient underwent a sever infection of HAdV and MP, and her pulmonary imaging showed progressive progression from left lower lung consolidation to left lung atelectasis despite aggressive treatment. What’s more, atelectasis of her left lung persist at least 1 year leading to recurrent respiratory infections, which needing resection of the left lung. It is important to analyze why our patient present with refractory atelectasis.

The obstructive type of atelectasis is most frequent in children [1]. According to the patient’s medical history, chest HRCT and the result of electronic bronchoscopy, both airway obstruction caused by foreign body, mucus plugs or endobronchiamass and compression of pulmonary parenchyma caused by intrathoracic mass, enlarged intrathoracic lymph nodes, pneumatosis pleura, effusion, chest wall defects or neuromuscular diseases have been ruled out. In the non-obstructive type of atelectasis, on the basis of medical history and genetic result, diseases altering alveolar surface tension include genetic disorders of surfactant dysfunction and pulmonary alveolar proteinosis, diseases that easily lead to recurrent infections, like cystic fibrosis, bronchiectasis and inborn errors of immunity (IEI) were also not support. As for genetic result, a heterozygous variants in the MUC5B gene were revealed. The gene MUC5B expresses the protein Mucin- 5B, expresses mainly in mucous cells of submucosal glands of airway tissues [12]. The MUC5B promoter mutation in humans induces proteostatic stress in the lung epithelium that activates the integrated stress response, precluding lung repair after injury, which is associated with familial interstitial pneumonia and idiopathic pulmonary fibrosis (IPF) [13, 14]. The mutation of our patient is not located on the promoter of MUC5B and there is no phenotype-associated short variants data for this region was reported. Combined with no progressive difficulty in breathing in the past time of the patient and no pulmonary fibrosis or pulmonary interstitial change in chest CT, IPF cannot be diagnosed. The most common cause of atelectasis is infection. Obviously, atelectasis in the early stage was caused by the infection of HAdVand MP. A previous study showed that clinical course before bronchoscopy, length of stay, bronchial mucus plug formation, age were optimal predictors of long-term atelectasis [3]. Of which, only one was met in our patient, total hospital stay were long. The longer the course of the disease, the more serious the destruction of the bronchial wall and irreversible structural remodeling are. In particular, our patient had an increased area of atelectasis eventually accumulated the entire left lung, other causes of refractory atelectasis need to be identified.

PIBO is most commonly associated with adenovirus infection: serotypes 3, 7, 11 and 21, also secondary to influenza, measles, MP and so on [15]. The diagnosis of PIBO is usually based on a combination of clinical features (persistent wheeze/cough and increased work of breathing following a previous severe lower respiratory tract infection), pulmonary function testing (obstructive ventilatory dysfunction) and radiological findings (mosaic attenuation consistent with variable degrees of airway obstruction and air trapping) [16]. The gold standard of diagnosis is lung biopsy with histopathological confirmation. The histopathological features of BO suggest that injury and inflammation of small-airway epithelial cells and subepithelial structures lead to excessive fibroproliferation, which is due to aberrant tissue repair, including ineffective epithelial regeneration, in response to tissue injury [16]. Therefore, our patient was diagnosed with BO demonstrably. The difference is that atelectasis still persisted, while mosaic sign gradually improved in our patient’s chest HRCT. Bronchiolitis obliterans with organizing pneumonia (BOOP) comes to mind for it shows bilateral or unilateral, patchy or large leaf consolidation in chest HRCT [15]. The diagnosis of BOOP mainly depends on the pathological examination of lung tissue. The characteristic pathological changes of BOOP are MASSON bodies at the end of respiratory bronchioles [17], which have not been found in the pathological findings of our patient.

As we all know, the mature alveolar epithelium consists of alveolar type I and type II cells, which occupy about 96% and 4% respectively of the surface [18]. Alveolar type II cells help to alveolar epithelial repair and regeneration as progenitors of alveolar type I cells as well as produce and recycle surfactant phospholipids and proteins as well as express innate immune molecules [19]. The main functions of pulmonary surfactant is lowering surface tension at the air–liquid interface and thus preventing alveolar collapse at end-expiration [20]. Some infection could impair the ability the surfactant has to adsorb to the surface and lower surface tension, which take part in the causes of atelectasis. Also, many studies have shown that alveolar type II cells dysfunction or dropout is associated with the pathogenesis of various parenchymal lung diseases, such as IPF, chronic obstructive pulmonary disease (COPD) and so on [19]. Our patient underwent refractory atelectasis leading to recurrent infection, bronchiolitis obliterans, and displacement of the mediastinum, so pneumonectomy has been preformed. But, the pathological findings of the resected diseased lung suggested the decrease of alveolar type I cells not alveolar type II cells. Alveolar type I cells are responsible for exchange gases with the adjacent capillary network, maintain ion and fluid balance at the air–liquid interface [21]. Although dysfunctional alveolar epithelium is implicated in almost every lung disease, the specific contribution of alveolar type I cells to disease development has not been evaluated in present studies.

The influence of different lung diseases in alveolar type I cells and alveolar type II cells is not all the same. During acute lung injury, alveolar type I cells are particularly susceptible to injury, and alveolar type II cells die in the presence of severe or certain types of injury [22]. As for chronic disease, such as, IPF is characterized by a loss of alveolar type I cells and dysfunctional alveolar type II cells [23], while, loss of secretory cells and dysplasia of alveolar type I cells are verified in BO [24]. Our patient was not in an acute infectious phase when accepted pneumonectomy, which eliminated acute infection lead to the loss of alveolar type I cells. Due to the absence of progressive dyspnea and pulmonary interstitial change in chest HRCT, it is not supported that the decrease of alveolar type I cells caused by IPF. Despite the clinical diagnosis of BO in our patient, she did not appear loss of secretory cells and dysplasia of alveolar type I cells as previous study shown. Therefore, it is worthy of our serious consideration that whether refractory atelectasis is related to the loss of alveolar type I cells. More cases of refractory atelectasis should be reported, and more attention should be paid to the number and function of alveolar epithelial cells in these patients, especially alveolar type I cells in the future.

In conclusion, we reported an immunocompetent patient gradually developed atelectasis of the left lung needing lobectomy after the infection of HAdV and MP. Although the lung biopsy confirm the diagnosis of PIBO, chest HRCT findings were atypical. At Last, lung tissue was analyzed by immunohistochemistry, which found type 1 alveolar epithelial cells decreased selectively. Whether the decrease of type I alveolar epithelial cells related to refractory atelectasis needs more evidences.

Abbreviations

BAL

Bronchoalveolar lavage

HAdV

Human adenovirus

MP

Mycoplasma Pneumoniae

CAP

Community-acquired pneumonia

PIBO

Post-infectious bronchiolitis obliterans

CRP

C-reactive protein

HRCT

High-resolution computed tomography

NGS

Next generation sequencing

BALF

Bronchoalveolar lavage fluid

WBC

White blood cells

TEM

Transmission electron microscopy

BOOP

Bronchiolitis obliterans with organizing pneumonia

IEI

Inborn errors of immunity

IPF

Idiopathic pulmonary fibrosis

COPD

Chronic obstructive pulmonary disease

Authors’ contributions

GL conceptualized and designed the study, drafted the initial manuscript as well as revised the manuscript. XX collected and analyzed the data as well as wrote the manuscript. HX analyzed the pathological results. HF made the treatment plan and collected data. XJ developed early treatment protocols and collected data.DY and DZ performed bronchoscopy and BAL.All authors reviewed the manuscript.

Funding

This work is supported by the National Natural Science Foundation of China (82370015 to G. L).

Data availability

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

Declarations

Ethics approval and consent to participate

The studies involving humans were approved by the Ethics Committee of Guangzhou Women and Children’s Medical Center, Guangzhou Medical University.

Consent for publication

The guardians of the patient provided written informed consent to use clinical and laboratory data from the patients’ medical reports.

Competing interests

The authors declare no competing interests.