key: cord-0785838-2i9p2laq
authors: Miró, Òscar; Llorens, Pere; Jiménez, Sònia; Piñera, Pascual; Burillo-Putze, Guillermo; Martín, Alfonso; Martín-Sánchez, Francisco Javier; García-Lamberetchs, Eric Jorge; Jacob, Javier; Alquézar-Arbé, Aitor; Mòdol, Josep Maria; López-Díez, María Pilar; Guardiola, Josep Maria; Cardozo, Carlos; Lucas Imbernón, Francisco Javier; Tejedo, Alfons Aguirre; García, Ángel García; Grinspan, Martín Ruiz; Roca, Ferran Llopis; González del Castillo, Juan
title: Frequency, risk factors, clinical characteristics and outcomes of spontaneous pneumothorax in patients with Covid-19: A case-control, emergency medicine-based multicenter study
date: 2020-11-20
journal: Chest
DOI: 10.1016/j.chest.2020.11.013
sha: 30fa405b2fa9222d46b73219741721a890bd2ac0
doc_id: 785838
cord_uid: 2i9p2laq

Background Recent reports of COVID-19 patients developing pneumothorax mainly correspond to case reports in mechanically-ventilated patients. The real incidence, clinical characteristics and outcome of spontaneous pneumothorax (SP) as a form of COVID presentation remains to be defined. Research question Do the incidence, risk factors, clinical characteristics and outcomes of SP in COVID-19 patients attending emergency departments (ED) differ compared to COVID patients without SP and non-COVID patients with SP? Study design and methods: This case-control study retrospectively reviewed all COVID patients diagnosed with SP(case group) in 61 Spanish EDs(20% of Spanish EDs) and compared them with two control groups: COVID patients without SP and non-COVID patients with SP. Relative frequencies of SP were estimated in COVID and non-COVID patients in the ED and annual standardized incidences were estimated for both populations. Comparisons between cases and controls included 52 clinical, analytical and radiological characteristics and 4 outcomes. Results We identified 40 SP in 71,904 patients with COVID-19 attending EDs(0.56‰, 95%CI=0.40-0.76‰). This relative frequency was higher than that of non-COVID patients(387/1,358,134, 0.28‰, 95%CI=0.26-0.32; OR=1.93, 95%CI=1.41-2.71). The standardized incidence of SP was also higher in COVID patients (34.2 versus 8.2/100,000/year; OR=4.19, 95%CI=3.64-4.81). Compared with COVID patients without SP, COVID patients developing SP more frequently had dyspnea and chest pain, low pulsioxymetry, tachypnea and increased leukocyte count. Compared to non-COVID patients with SP, cases differed in 19 clinical variables, the most prominent being a higher frequency of dysgeusia/anosmia, headache, diarrhea, fever and lymphopenia (all with OR>10). All the outcomes measured, including in-hospital death, were worse in cases than in both control groups. Interpretation SP as a form of COVID presentation at the ED is unusual (<1‰ cases) but is more frequent than in the non-COVID population and could be associated with worse outcomes than SP in non-COVID patients and COVID patients without SP.

Background: Recent reports of COVID-19 patients developing pneumothorax mainly correspond to case reports in mechanically-ventilated patients. The real incidence, clinical characteristics and outcome of spontaneous pneumothorax (SP) as a form of COVID presentation remains to be defined.

Research question: Do the incidence, risk factors, clinical characteristics and outcomes of SP in COVID-19 patients attending emergency departments (ED) differ compared to COVID patients without SP and non-COVID patients with SP? Study design and methods: This case-control study retrospectively reviewed all COVID patients diagnosed with SP(case group) in 61 Spanish EDs(20% of Spanish EDs) and compared them with two control groups: COVID patients without SP and non-COVID patients with SP. Relative frequencies of SP were estimated in COVID and non-COVID patients in the ED and annual standardized incidences were estimated for both populations. Comparisons between cases and controls included 52 clinical, analytical and radiological characteristics and 4 outcomes. . Compared with COVID patients without SP, COVID patients developing SP more frequently had dyspnea and chest pain, low pulsioxymetry, tachypnea and increased leukocyte count. Compared to non-COVID patients with SP, cases differed in 19 clinical variables, the most prominent being a higher frequency of dysgeusia/anosmia, headache, diarrhea, fever and lymphopenia (all with OR>10). All the outcomes measured, including in-hospital death, were worse in cases than in both control groups.

Infection by SARS-Cov-2 is mainly characterized by fever and respiratory symptoms, with dyspnea and lung infiltrates being present in more than 50% of hospitalized cases 1 . A significant number of other signs and symptoms can be present, involving the gastrointestinal tract, hepatic inflammation, myalgia and rhabdomyolysis, neurological symptoms such as dysgeusia and anosmia, or a pro-coagulant state, biochemically detected by increased D-dimers and related to complications and worse prognosis [1] [2] [3] [4] . In some patients, some of these entities appear after the patient has been admitted and, to some extent, represent the increased number of complications that may be presented by patients who are bedridden, multidrug treated and/or in very poor condition. In this scenario, it is difficult to quantify the real association of a certain manifestation with the pathogenesis of the disease caused by SARS-Cov-2 infection.

Spontaneous pneumothorax (SP) is a potential complication in some pulmonary infections, and it is especially frequent in Pneumocystis jirovecii pneumonia (PCP) 5 . The real incidence of SP in patients with COVID-19 is currently unknown. Some sporadic cases of patients with COVID-19 developing pneumothorax have been reported [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] . In some of these cases, invasive or non-invasive mechanical ventilation was applied prior to the development of pneumothorax 8, 11, 15, 16, 17 , while in other cases it appeared after several weeks of pulmonary involvement, with large inflammatory infiltration and cyst formation in pulmonary parenchyma 8, 11, 12 . Indeed, only a few case-series have described the frequency of pneumothorax in COVID-19, being reported as being present in 1% of 99 hospitalized patients 2 , in 3% of patients hospitalized with pneumonia 17 , in 6% of 202 mechanically ventilated patients 6 and in 1% of 91 deceased patients 7 . For most of these patients, non-invasive or invasive mechanical ventilation probably contributed to this relatively high incidence. In the present study, we aimed to investigate the frequency of SP in patients attended in the emergency department (ED), before hospitalization and treatment with specific drugs for SARS-Cov-2 infection and before the initiation of ventilatory support.

The specific objectives were: 1) to determine the relative frequency of SP in patients with COVID-19

coming to the ED as well as estimate the annual standardized incidence; 2) to uncover the risk factors and analyzed the protocol, and finally 61 (20% of Spanish EDs) consented to participate and duly sent all the data required ( Figure 1 ). Altogether, these 61 hospitals provide health coverage to 14,537,000 citizens (31%of the population of 46.9 million of Spain) and make up a balanced representation of the Spanish territory (representing 12 of the 17 Spanish autonomous communities), type of hospital (community, reference and high-technology university hospitals were included) and involvement in pandemic (with EDs attending from 1% to 47% of the ED census during the COVID outbreak period corresponding to COVID patients) 18 .

The investigation of SP in COVID patients, one of the entities included in the UMC-19 project, was labeled as UMC-19 Study 7 (UMC-19-S 7 ) and consisted of a retrospective, case-control, multicenter study that reviewed the medical reports of COVID patients attended and diagnosed with SP during ED assessment and management in Spanish EDs before hospitalization. As the UMC-19-S 7 was conceived as an exploratory study, sample size was not predetermined.

The case group was formed by COVID patients, with the diagnosis of SP being made on the basis of chest X-ray or thoracic computerized tomography (CT). All SPs were confirmed by radiologists and/or thoracic Controls of the UMC-19-S 7

We defined two different control groups. One group was formed by COVID patients (without SP)

attending the ED during the same COVID outbreak period used for case inclusion (March 1 st to April 30 th , 2020). As the number of COVID patients with SP included in the UMC-19-S 7 study was expected to be very low, we planned to select 10 COVID patients for every case detected by each center, in order to maximize the statistical power as much as possible. Selection was performed by the inclusion of the 5+5 COVID patients seen immediately before and after each case included by the center. This group, named control group A, was specifically designed to uncover the risk factors associated with SP development in COVID patients. aminotransferase -AST-, lactate dehydrogenase -LDH-, procalcitonin, hemoglobin, leucocytes, lymphocytes, D-dimer) and 8 radiological findings in chest X-ray (cardiomegaly, pleural effusion, interstitial lung infiltrates and ground-glass opacities, and location, extension and accompanying pneumomediastinum and subcutaneous emphysema in patients with pneumothorax). All these variables were collected from retrospective review of all patient medical reports obtained during ED and hospital stay.

We defined 4 different outcomes for cases and controls which consisted in: 1) the need for hospitalization; 2) the need for admission to intensive care; 3) prolonged hospitalization (defined as a length of stay >7 days, which is the median length of stay of hospitalized patients in Spain); and 4) inhospital all-cause mortality. Outcomes were determined after retrospective review of all patient medical reports obtained during ED and hospital stay. Outcomes adjudication was made by the principal investigator of each center without external review.

Discrete variables were expressed as absolute values and percentages, and continuous variables as mean and standard deviation (SD) or median and interquartile range (IQR) if not normally distributed.

The relative frequency of SP was expressed per thousand (‰) of COVID or non-COVID patients coming to the ED, and the annual standardized incidence was expressed per 100,000 COVID or non-COVID individuals. Both estimations were made with 95% confidence intervals (CI) that were calculated using the exact method for binomial distributions. To estimate the COVID and non-COVID population in each ED catchment area, we used the seroprevalence of SARS-CoV-2 in the province where the ED was located. These detailed seroprevalences were determined in a wide Spanish study performed between 

The mean age of the COVID patients with SP (cases) was 66 years, 73% were males, 20% had asthma, 10% chronic obstructive pulmonary disease, and 10% were active smokers. The most frequent symptomatology was dyspnea (88%), cough (53%), chest pain (40%) and fever (38%), and the median time from symptoms onset to ED consultation was 5 days. The remaining clinical characteristics, as well as the vitals at ED arrival and laboratory findings are presented in Table 1 . Cardiomegaly and pleural effusion were rarely seen in these patients (in 11% and 3% X-rays, respectively), but interstitial lung infiltrates and ground-glass opacities were frequently observed (in about half of the patients). The location of SP was in the right lung in 77% of cases, with an extension ranging from minimal to massive, and was accompanied by pneumomediastinum and subcutaneous emphysema in 16% of cases (Table 1) .

In 3 cases and 15 patients of control group B, chest X-ray was not performed in the ED, and SP diagnosis was made by thoracic CT.

Some statistically significant differences were found when cases were compared with controls, (Table 1) , and the magnitudes of these associations are shown in Table 2 . Remarkably, the complaint of dyspnea at ED arrival was the clinical characteristic of COVID patients associated with the highest risk of presenting concomitant SP (OR=5.90; 95%CI=2. 27-15.4 ). Additionally, SP was also found to be associated with more chest pain, tachypnea and hypoxia, and higher leukocyte count. All these associations remained statistically significant in the sensitivity analysis including only COVID patients with SARS-CoV-2 infection confirmed by RT-PCR ( Table   2 ).

Nearly all the outcomes measured were worse in the cases than in the two control groups ( Figure 3) .

Specifically, COVID patients with SP had an adjusted OR (for age, sex and center) for in-hospital mortality (Table 3) .

We found that 0.56‰ of COVID patients coming to the ED had SP, and we estimated an annual standardized incidence of 34.2 SP per 100,000 COVID patients. Both the relative frequency in ED comers and the standardized incidence found during the 2-month period of the COVID outbreak in Spain were higher than those observed in the non-COVID population. We consider our results to be quite reliable, as some of our figures found in the general population (not infected by SARS-CoV-2) match previously reported data. On one hand, the relative frequency of SP among ED comers reported in a previous

Italian study was of 0.42‰ 20 , which is similar to that found in the non-COVID general population in the Spanish EDs participating in the present study (0.28‰). On the other hand, the standardized incidence per 100,000 population each year of primary SP has been reported to be between 7.4 to 18 cases in males, and 1.2 to 6 cases in females 21, 22 , being values which are also close to the standardized incidence of 8.2 found in the present study. Remarkably, our study did not include cases of SP appearing after the initiation of invasive or non-invasive mechanical ventilation, a circumstance that increases the risk of pneumothorax in patients in general and in patients with lung infections in particular 23, 24 . Therefore, the increased OR of 1.93 for the relative frequency of SP in the ED and of 4.19 for the standardized incidence in the general population found for COVID patients in the UMC-19-S 7 represents the first evidence that SP is probably a consequence related to SARS-CoV-2 infection and, in fact, COVID-19

should be added to the list of etiologies of secondary SP. The main facilitating entity of secondary SP is chronic obstructive pulmonary disease, and especially lung emphysema, which are present in more than 50% of cases [25] [26] [27] . Of note, with respect to the control groups, this entity was not overrepresented in our cases, reinforcing the role of COVID infection itself in SP development. In fact, SP can complicate the course of necrotizing pneumonia due to P.jirovecii, lung tuberculosis and, less often, fungi or other microorganisms 5, 26, 28 .

The presumed common mechanism underlying SP in patients with lung infection is direct invasion and necrosis of lung tissue including the pleura by the microorganism itself. However, other factors could facilitate SP development. In patients with HIV-related P. jirovecii, in whom the frequency of SP is around 10‰ (more than 10-fold higher than what we reported for COVID patients), it has been hypothesized that the administration of aerosolized pentamidine may increase the likelihood of PCP to grow and cause cavitation in the peripheral parts of the upper lobe, thereby increasing the risk of pneumothorax 5, 28 . In addition, inflammatory reaction could also contribute to SP during lung infections.

Some studies have reported that SARS might independently result in cyst formation, even in the absence of mechanical ventilation, and inflammatory exudate could play a relevant role in this 29, 30 .The pathological features in lungs of patients with COVID-19-related pneumonia greatly resemble those seen in SARS and Middle Eastern respiratory syndrome coronavirus infection 31, 32 . Recent histological examinations reported diffuse bilateral alveolar damage with cellular fibromyxoid exudates in COVID-19, and pulmonary cystic lesions. Pulmonary cystic lesions may develop in response to cellular fibromyxoid exudates, which form a valve in the bronchus 33 . In fact, the cytokine storm syndrome, a critical clinical J o u r n a l P r e -p r o o f condition induced by a cascade of cytokine activation, characterized by overwhelming systemic inflammation, hyperferritinaemia, haemodynamic instability and multiple organ failure, is now recognized to being a main cause of the severity of SARS-CoV-2 infection 34 . It could, therefore, be hypothesized that patients with higher inflammatory response in SARS-CoV-2 infection could be at a higher risk of developing lung damage favoring SP. Our study measured a reduced number of inflammatory biomarkers (as this was not its main objective) and, although we found significantly higher leucocyte blood counts in COVID patients that developed SP, CRP, procalcitonin and D-dimers did not significantly differ. Therefore, further studies specifically designed to test this hypothesis are needed.

COVID patients developing SP more frequently presented dyspnea, tachypnea and hypoxia, but all these features are very common in severe COVID patients. Interestingly, chest pain was remarkably more present in connection with SP development. On the other hand, the distinctive clinical characteristics of SP in COVID patients with respect to SP in the general non-COVID population are older age, and a higher frequency of diabetes mellitus and hypertension (probably related to the more advanced age of the COVID population). Regarding the clinical picture, symptoms derived from SARS-CoV-2 infection itself were by large the most distinctive features (including dysgeusia, headache, fever, diarrhea and anosmia). On the other hand, symptoms lasted longer when patients consulted to the ED (a median of 5 days in COVID patients versus 1 day in non-COVID patients, again in connection with COVID-19 rather than with SP), and while dyspnea, tachycardia, tachypnea and hypoxemia were more frequent in COVID patients, chest pain was a less frequent complaint in this population.

All the outcomes assessed in the UMC-19-S 7 were worse for COVID patients with SP compared to the two control groups (with the exception of the need for hospitalization with respect to the control group B). COVID-19 itself was responsible for the poorer prognosis of SP in COVID patients compared to the general population, especially in terms of the huge increase observed in in-hospital mortality (OR of 15).

In addition, it should also be taken into account that the former group was older than the latter (median age of 66 vs. 36 years), and age is always a main driver of mortality. Conversely, it is difficult to attribute SP to the increment of in-hospital mortality observed in COVID patients with SP compared to COVID patients without SP. COVID patients developing SP may have been the most severe patients, in terms of viral infection and, especially, in terms of inflammatory response. The relatively small sample size of our study precludes adjustment for variables linked to the severity of COVID-19. Therefore, despite finding statistically significant differences, we could not rule out that this apparent increase of risk for COVID patients developing SP was due of the clinical characteristics of COVID-19 itself rather than to SP, and caution should be taken when interpreting differences in outcomes in COVID patients with and without SP.

This study has several limitations. First, SP was only detected if a chest X-ray or CT was performed in the ED. However, during the COVID-19 pandemic, emergency physicians had a very low threshold for J o u r n a l P r e -p r o o f ordering chest imaging, and an X-ray or CT was performed in the vast majority of COVID patients, especially if respiratory symptoms were manifested. Second, inadvertent SP might have occurred, although in many centers a senior radiologist reviewed the imaging studies. Third, some mildly symptomatic cases of SP, especially in non-COVID patients, could have remained at home during the COVID-19 outbreak due to fear of COVID-19 contagion. The standardized incidence of SP in non-COVID patients during the pre-COVID period was almost double that found during the COVID period suggesting that this fact probably existed. Nonetheless, even when the relative frequency of SP in the ED and the standardized incidence in the general population for SP in COVID patients were specifically compared with those found in non-COVID patients during the pre-COVID period, the differences still remained statistically significant. Fourth, we did not adjust the incidence of SP in COVID for all relevant patientrelated or disease-related factors influencing the relative frequency of SP presentation and outcomes, and this could somewhat alter the estimations presented in the current study. Fifth, in about one quarter of the cases COVID-19 diagnosis was based on clinical and/or radiological findings, with no microbiological confirmation. Although these were the figures in most countries during the outbreak due to shortage of tests 35, 36 , there could be a bias of misclassification in the COVID group for some of these cases. Nonetheless, as the sensitivity analysis that compared only COVID patients (with and without SP) with microbiological confirmation of SARS-CoV-2 infection provided very similar results as the main analysis, we believe that this bias was not large in magnitude. Additionally, some COVID patients with SP that were asymptomatic with respect to SARS-CoV-2 infection could have been misclassified into the non-COVID group. Sixth, although 61 EDs participated in the present study, the number of cases (COVID patients with SP) was very low. This is a major limiting factor to this study (although not preventable) and means that all the factors associated with SP in COVID patients were very imprecisely estimated, as the confidence intervals were very wide. Seventh, as a retrospective study, although the case record form was standardized, there was no monitoring of data collection methods, and diagnosis and outcome adjudication were done locally. Finally, although the UMC-19-S 7 involved 61 EDs, it was carried out in a single country and external validation in other countries is needed before generalizing our findings.

Despite these limitations, we conclude that the incidence of SP in COVID patients attending the ED is low but increased with respect to non-COVID patients. Therefore, SARS-CoV-2 infection may have a direct role in this increased incidence. COVID patients complaining of dyspnea and chest pain, and exhibiting tachycardia, tachypnea and hypoxemia should be assessed to rule out SP.

J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f Table 3 : Sensitivity analysis for comparison between cases (COVID patients with spontaneous pneumothorax) and control A patients (COVID patients without spontaneous pneumothorax) with respect to the significant clinical differences and outcomes using only cases and controls with microbiological confirmation of SARS-CoV-2 infection.

Odds ratio for cases respect to control A patients (95% CI) 

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