Mediastinal Emphysema as a Speciﬁc Complication of COVID-19 (Case Report)

The aim of the paper. To provide clinical case descriptions and approaches to the management of patients with spontaneous pneumomediastinum in COVID-19 associated pneumonia, as they are not addressed in the current clinical guidelines, and therefore are worthy of special attention. Among 224 patients with laboratory-conﬁrmed diagnosis of the novel coronavirus infection COVID-19, ﬁve cases of pneumomediastinum without pneumothorax were identiﬁed. Of these, in two cases the pneumomediastinum developed during noninvasive lung ventilation (NLV) (one case) and invasive lung ventilation (one case). In three cases, spontaneous mediastinal emphysema was not associated with lung ventilation. By the time of publication, one case of pneumomediastinum was completed, and four patients remained hospitalized. All ﬁve patients were males aged from 52 to 84 years. This paper presents in depth the description of two cases of mediastinal and subcutaneous emphysema in patients with COVID-19. interest. Authors declare no competing interests.


Introduction
More than a year has passed since the first human cases of SARS-CoV-2 occurred and the new coronavirus infection (COVID19) pandemic was announced by the World Health Organization on March 11, 2020 [1]. As of July 2020, there were more than 15.7 million cases of infection and more than 640,000 deaths from COVID-19 worldwide [2].
Spontaneous pneumomediastinum (SP), or spontaneous mediastinal emphysema (SME), is an uncommon condition characterized by air infiltration into mediastinal spaces and soft tissues of the anterior chest wall [3,4]. Lack of clear evidence of mediastinal organ damage and pneumothorax is characteristic for SP, resulting in difficulties in differential diagnosis and treatment choice. According to several studies, SME is more typical for young men [4,5].
This paper presents clinical observations of SP in patients with COVID-19 associated pneumonia treated at the Lomonosov MSU Medical Research and Education Center.
Between April 21 and June 13, 2020, 224 patients with laboratory-confirmed diagnosis of novel coronavirus infection COVID-19 were treated at the hospital. SP without pneumothorax was diagnosed in 5 patients. In 3 cases SP developed in spontaneously breathing patients, in 2 patients SP was diagnosed during noninvasive (n=1) and invasive lung ventilation (n=1). All patients were male, aged 52 to 84 years.
The aim of the paper -to provide clinical case descriptions and approaches to the management of patients with spontaneous pneumomediastinum in COVID-19 associated pneumonia, as they are not addressed in the current clinical guidelines [6,7], and therefore are worthy of special attention.

Clinical case 1
A 52-year-old man was hospitalized 3 days after the onset of the disease complaining of fatigue, chest pain, dry cough, dyspnea at rest, and elevated body temperature over 38.5°C.
The treatment administered in the infectious disease ward is presented in the table.
On day 4, the patient had progression of respiratory failure and cough with corresponding increase of lung tissue involvement according to chest CT (multiple bilateral ground-glass opacities transforming into consolidation and «crazy-paving» pattern with air bronchograms) in up to 30-35% of total area ( fig. 1, a). The patient was started on methylprednisolone 1000 mg/day pulse therapy. On day 8, due to worsening respiratory failure, reduced tissue oxygenation index (TOI) (down to 121 mm Hg), the patient was transferred to intensive care unit (ICU), where noninvasive lung ventilation (NLV) was started through a face mask in a CPAP mode and following parameters: Pinsp 16 mBar, PEEP 5 mBar. The duration of NLV was 8 days. Spiral chest CT performed one day after the weaning demonstrated no consolidation with air bronchograms ( fig. 1, b). The total area of involved lung tissue increased from 30-35% to 85-90% due to bilateral diffuse «ground-glass» thickening areas with reticular pattern.
On day 20, the chest CT revealed pneumomediastinum with no free air in the pleural cavities ( fig. 1, c). Considering lack of new complaints and overall improvement in the patient's condition, the treatment was continued without modifications. On day 28, the follow-up study demonstrated a significant increase in the pneumomediastinum size (spreading to the lower mediastinum), severe emphysema of soft tissue of the neck, moderate emphysema of right chest wall soft tissue (anterior, lateral and posterior regions) and involved lung area reduced down to 75%.
The treatment remained unchanged; the patient had no symptoms of pneumomediastinum. Chest CT on days 31 and 36 revealed spontaneous regression of pneumomediastinum and reduction of the involved area down to 60%.

Clinical case 2
A 76-year-old man was admitted to hospital with complaints of elevated body temperature up to 39.0ºC, fatigue, dry cough, difficulty in breathing. During the week prior to hospitalization, he received antiviral and antibacterial therapy. He was hospitalized due to ineffective treatment and CT signs of viral pneumonia progression with increase in involved lung area from 25% to 60% over 10 days.
The diagnosis was confirmed by PCR of nasopharyngeal and oropharyngeal secretions.
The treatment administered in the infectious disease unit is shown in Table 1.
Due to respiratory failure progression (TOI 111 mm Hg) the patient was transferred to ICU and put on NLV through face mask in CPAP mode with the following parameters: PS (pressure support) 10 mbar, PEEP (positive end-expiratory pressure) 5 mbar. Corticosteroid therapy was initiated.
However, despite modified ventilation parameters, progression of subcutaneous emphysema of the neck, supraclavicular and axillary areas was noted. Laryngoand tracheobronchoscopy, esophagoscopy ruled out tracheal, bronchial, or esophageal lesions. Pneumomediastinum onset preceding initiation of mechanical ventilation and tracheostomy allowed to exclude tracheal membranous wall injury during tracheotomy.

Результаты и обсуждение
В диагностике спонтанного пневмомедиастинума (или эмфиземы средостения) ведущее место занимает исключение наиболее частых причин дислокации воздуха в мягкие ткани Despite the drainage, the patient remained critically ill for 8 days. Subcutaneous emphysema spread to the scrotum and anterior surface of the thigh (Fig. 2, d, 27 days after the disease onset), and owing to severe lung involvement further surgical intervention was deferred. Mediastinal drainage tube was removed on the 3rd day after intervention, repeated tracheostomy was performed.
Later, along with the progression of the lung tissue involvement (Fig. 2, e, day 32), there was a gradual spontaneous resolution of subcutaneous emphysema and pneumomediastinum (Fig. 2, f, day 37).
Despite the obvious improvement of mediastinal emphysema according to chest CT, the patient remained critically ill; no signs of lung lesion resolution were noted either. On day 51, the patient died because of progressive multiple organ failure due to sepsis.

Results and Discussion
When diagnosing SP (or mediastinal emphysema, SME), it is essential to rule out the most frequent causes of air displacement into the mediastinal soft tissues, which are esophageal and tracheal injuries. In routine clinical practice, SME can be commonly caused by spontaneous ruptures of paramediastinal bullae and lung areas, which often occur without pneumothorax and may cause differential diagnosis challenging. Widespread occurrence of viral pneumonias and, as a consequence, severe interstitial lung abnormalities, have led to a significant increase in the number of patients with SME.
By early 2021, a considerable experience had been accumulated in the management of patients with SME associated with COVID-19. There have been several dozens of publications describing individual cases of such patients, but they lack a systematic, full description of the clinical and laboratory presentations, which significantly limits the interpretation and analysis of available clinical data. Some studies presented a brief history of the disease, list the main components of drug treatment, and assess complete blood count and C-reactive protein level [15].
During 3 months of treatment of patients with viral pneumonia associated with COVID-19 infection at the Lomonosov Moscow State Medical Center, SP was detected in 5 (2.23%) patients out of 224.
According to the most common theory of SP pathogenesis proposed by C. C. Macklin in 1939, a sudden increase in intrathoracic pressure leads to a rise in intraalveolar pressure [16]. The pressure gradient occurring at the border of alveolar lumen and pulmonary interstitium causes the rupture of interalveolar septa with air bubbles spreading mainly perivascularly towards the lung root [5]. When a single increase in intra-alveolar pressure occurs, after air migration into the interstitium the pressure gradient decreases, the area of alveolar rupture undergoes «adhesion» and reparation, followed by resorption of the gas mixture from the interstitium [13].
The mechanism of SME development in COVID-19 probably does not differ from that described by C. C. Macklin [16], however the need to maintain sometimes high positive end-expiratory pressure and plateau pressure in case of lung ventilation, which prevents the pressure gradient between alveoli and interstitial lung tissue from decreasing, is a specific feature of pneumomediastinum in COVID-19.
The treatment strategy for patients with spontaneous pneumomediastinum is mostly conservative and includes bed rest, anesthesia, and oxygen therapy [8]. Antibiotic therapy is not indicated unless there is clinical evidence of mediastinitis. Tension pneumomediastinum with progressing respiratory failure, as well as infection of soft tissues of mediastinum with mediastinitis can become an indication for surgical treatment. When indications for surgical treatment arise, upper mediastinotomy according to Tiegel with tunnelization of pretracheal tissue to the level of tracheal bifurcation and active drainage of mediastinum are considered to be the methods of choice [3]. нительной коррекции. К сожалению, в данной публикации также не указаны изменения маркеров воспаления или повреждения тканей.
Тактика лечения пациентов со спонтанным пневмомедиастинумом преимущественно консервативная и включает постельный режим, обезболивание и оксигенотерапию [8]. Назначение антибактериальной терапии в отсутствие клинического подтверждения медиастинита не показано. Показанием к According to C. M. Chu et al. [17], the incidence of SME in SARS from March to April 2003 was 11.6% among 112 cases with confirmed SARS CoV, while the overall incidence of pneumomediastinum was about 2%. In the group of patients with SME, medication regimens did not differ from the main population. Blood lactate dehydrogenase (LDH) level was the only laboratory indicator, whose elevation was associated with SME development. SP was a predictor of more frequent tracheal intubation and increased mortality. Four patients underwent mediastinal drainage. Small size of the study group doesn't allow to draw any definite conclusions concerning possible prevention and the most rational management of the condition. Several studies have discussed the advantages of the «safe ventilation» in the management of patients with severe pneumonia, including nosocomial [18,19], but best treatment approaches to such complications as mediastinal emphysema still remain unexplored.
To date, the management of patients with SME associated with the novel coronavirus infection COVID-19 is still not covered by international clinical guidelines; however, there are studies attempting to analyze global experience in order to develop some unified approach to managing patients with such COVID-19 complications as pneumothorax, mediastinal emphysema, and pneumatocele [20]. As preventive measures of the SP, A. Sihoe [20] suggests adherence to «safe ventilation» principles in COVID-19 [7], i. e. maintaining safe volumetric values (4-8 ml/kg) and plateau pressure (less than 30 cm H 2 O). The authors do not describe the surgical options for correction of spontaneous pneumomediastinum but suggest considering pleural cavity drainage in any pneumothorax regardless of its etiology.
A. Sihoe et al. acknowledge [20] that it is currently difficult to accurately assess the incidence of SME in a novel coronavirus infection but estimate it at 2% based on earlier work by X. Yang et al. who reported the first cases of SARS-COV-2 in Wuhan [21]. Notably, Yang reported rather a 2% incidence of pneumothorax (1 of 52 patients with SARS-COV-2) rather than the actual incidence of SME.
Inadequate statistical data on the prevalence of SME could be due to the controversial issue of case reporting in pneumomediastinum during mechanical ventilation. Thus, C. M. Chu, Y. Y. Leung et al. recorded SME only in patients not on ventilator [17]. The pathogenesis of pneumomediastinum development is the same regardless of ventilator use, but mediastinal emphysema during mechanical ventilation is usually considered to be a barotrauma manifestation requiring urgent interventions such as mediastinal decompression [22][23][24].
A. Sihoe и соавт. признают [20], что в настоящий момент точная оценка частоты встречаемости СЭС при новой коронавирусной инфек-Lack of symptoms and laboratory changes during development and resolution of pneumomediastinum (WBC count 10-14,000/µl, without left shift in the differential, C-reactive protein level 5-7 mg/l during the monitoring period) was a distinctive feature of the first case described above. Increased blood LDH levels in patients with SME described by C. M. Chu, Y. Y. Leung et al. [17] were not observed.
To describe the mechanism of spontaneous resolution of pneumomediastinum in case 2 patient, we formulated the following hypothesis. The pressure gradient equalization between alveoli and interstitium occurr due to worsened ventilation of the lung area, where lung tissue rupture has primarily occurred (the negative changes in lung tissue lesions during the observation period is noteworthy). Such a rapid reversal of pneumomediastinum and subcutaneous emphysema after cessation of gas inflow into the tissue can be explained by a high fraction of oxygen in the inhaled gas mixture (80-90%). Surgical treatment was performed in one patient, but the apparent lack of effect of surgical decompression of the mediastinum and spontaneous resolution of pneumomediastinum occurring later seem remarkable. This fact casts doubt on the validity of surgical treatment of patients with spontaneous pneumomediastinum.

Conclusion
SME is an uncommon specific complication of pneumonia caused by the novel coronavirus infection COVID-19, which, regardless of its direct cause, may represent a poor prognostic factor and predictor of a severe disease.
The main measures to prevent SME include adherence to the principles of safe ventilation such as limitation of volume (4-6 ml/kg) and plateau pressure index less than 30 cm H 2 O), as well as a rigorous risk-benefit assessment of the ventilation mode used.
Accidental detection of SME when there is a visible clinical effect from the treatment should not prompt the doctors to modify the treatment regimen, and especially to discontinue the steroids.
If SME is detected in a clinically stable patient, it is very likely to resolve spontaneously without specific treatment. Surgical treatment may be indicated if tension pneumomediastinum or signs and symptoms of mediastinitis, as well as clinically significant concomitant pneumothorax develop.
The questionable evidence of the risk of an additional mechanism of SARS-CoV-2 propagation when performing pleural drainage [25] should not be a reason for withholding pleural drainage if indicated.
When SME develops in a patient on the ventilator, it becomes a limiting factor that does not allow intensivist to set stricter modes of ventilation, if necessary.