In this study, we reported the clinical manifestations of patients with aPAP after infection with Omicron variants of SARS-CoV-2 for the first time. We found that aPAP patients with worse baseline respiratory status were more likely to have oxygen desaturation after COVID-19 infection, which means that such patients are more likely to have relatively serious symptoms such as dyspnea or worse prognosis after COVID-19 infection. In addition, we first reported the hospitalization rate of patients with aPAP after infection with Omicron strain, which was lower than the previously reported hospitalization rate of PAP patients infected with COVID-19[5].
Our study found that the infection rate of COVID-19 in aPAP patients was a little bit higher than that estimated by the Chinese Center for Disease Control and Prevention (CDC) in the same period. The infection rate of COVID-19 in aPAP patients in this study was 95.12%, while the CDC estimated that the infection rate of COVID-19 in China was 82.4% as of February 7, 2023[12]. We believe that this is likely due to the estimated results of the CDC through online survey. A considerable part of the population directly took non-steroidal anti-inflammatory drugs due to fever or other symptoms after COVID-19 infection, and did not report the infection, which may underestimate the infection rate of the COVID-19 pandemic in China. Meanwhile, a retrospective cohort study in Europe found that the infection rate of PAP patients was similar to that of the general population[5]. Therefore, we believe that aPAP does not increase the probability of COVID-19 infection in patients.
The main finding of this study was that patients with poor baseline respiration have a higher probability of hypoxia after COVID-19 infection. Previous research has not mentioned this point. Our study found that the indicators indicating the baseline respiratory status of patients with aPAP, previous oxygen therapy, PO2, DLCO/VA%, 6MWD, SGRQ total score, DSS categories, all of which showed that patients with poor baseline respiratory status were more likely to have oxygen saturation decline after COVID-19 infection. This is of great significance for the treatment of PAP patients and even patients with other interstitial lung diseases after infection with COVID-19. When patients with COVID-19 develop hypoxemia, it often means the progression of COVID-19, more serious symptoms, and worse prognosis. Therefore, for those PAP patients with poor baseline respiratory condition, when they are diagnosed with COVID-19 infection, doctors should pay more attention and take more active treatment strategies to avoid disease progression.
Another important finding was our study first reported the hospitalization rate of patients with aPAP infected with Omicron strain. Only 4 out of 39 patients were hospitalized, and the hospitalization rate was 10.3%, which is much lower than the previous reported in the European cohort with the rate of 35.5%. Meanwhile, all hospitalized patients in this study did not need ICU admission, and none of our patients died or need lung transplantation. However, almost 50% of hospitalized patients in the European cohort entered the ICU. Besides, there were also 2 out of 11 hospitalized patients died and 1 out of 11 hospitalized patients underwent lung transplantation[5]. This huge difference between the two studies may be caused by a variety of factors. Firstly, none of the patients in the European cohort study were vaccinated, while the vaccination rate of patients in our study was 71.8%. Although it was not found in our study that the dose of vaccination had a significant difference on whether patients would suffer from hypoxia after COVID-19 infection, a large number of previous studies have shown that vaccination can provide a very high level of protection and effectively reduce the rates of severity and mortality after COVID-19 infection[13]. Secondly, the SARS-CoV-2 strains infected by the patients in this study were all Omicron strains, while the European cohort did not mention what their infected strains were. Based on the enrollment time, it is speculated that the European cohort may be infected with Alpha or Delta strains, and Omicron strains should not be included. Different strains of the SARS-CoV-2 can lead to different infection and severity rates. Although the 10.3% hospitalization rate is not as high as expected, it is still relatively high compared to the general population (less than 1%), highlighting the vulnerability of the PAP population and the need for more attention after infection[14].
Our single-center study found that aPAP patients infected with COVID-19 in our cohort rarely used antiviral therapy. One out of 2 patients receiving antiviral therapy was hospitalized. Patients with high viral load of SARS-CoV-2 are more likely to develop severe disease, and early inhibition of viral replication can significantly improve the prognosis of patients with COVID-19[15, 16]. PAP patients with worse baseline respiratory status are more prone to hypoxia after infection, so we’d like to suggest that PAP patients prescribe timely antiviral therapy.
GM-CSF plays a key role in host lung defense. The presence of anti GM-CSF antibodies in patients with aPAP leads to a reduction in the ability of alveolar macrophages to clear debris and pathogens, maintain surfactant homeostasis, and limit inflammation in the alveolar environment[17]. A study of inhaled GM-CSF in the treatment of COVID-19-related hypoxemia found that inhaled GM-CSF treatment could effectively improve A–aDO2 in patients[7]. The European cohort study found that previous inhalation of GM-CSF treatment had no effect on the outcome or hospitalization of PAP patients infected with COVID-19, which is consistent with our findings[5]. There was no significant difference in the decrease of blood oxygen saturation no matter whether GM-CSF inhalation therapy was used in the past (P = 0.299), or GM-CSF inhalation therapy was continuously used or discontinued after covid-19 infection (P = 0.222). Therefore, whether inhaled GM-CSF treatment has benefits for PAP patients with COVID-19 still needs to be explored.
As an interstitial lung disease, doctors should take different treatments and monitoring strategies for PAP patients infected with COVID-19 according to different conditions. An international multicenter study showed that patients with interstitial lung disease had higher mortality after infection with COVID-19 compared with patients without interstitial lung disease or other chronic lung diseases[4]. However, data on COVID-19 in rare lung diseases are still scarce. Although a European cohort study showed that PAP patients had higher hospitalization rate and mortality after infection[5], but there still lacks of guideline or standards for PAP patients to better cope with COVID-19 in the current medical system. Our research fills this gap well. PAP patients simultaneously infected with COVID-19 has the risk of aggravating COVID-19. For patients with mild PAP, the risk of progression of COVID-19 is not much. However, for patients with higher DSS and more severity of PAP, the probability of oxygen desaturation greatly increases. Vaccination, timely oxygen therapy, early use of antiviral medication, and timely vital sings monitoring may minimize the disease progression of patients. It’s urgent to establish a treatment strategy for patients with PAP after infected with COVID-19 in the future.
There are some limitations in this study. Due to the fact that PAP is a rare lung disease and this study is a single center study, the number of PAP patients eligible for inclusion in the study is relatively small. In addition, due to the COVID-19 pandemic, many PAP patients have not been followed up in the past year due to the lockdown policy. This may lead us to underestimate the probability of serious events occurring in PAP patients infected with COVID-19. Although multivariate analysis was carried out, due to the limited number of patients and oxygen saturation decrease events, we only found DSS as a predictor to predict the possibility of patients' oxygen saturation decline. Whether PAP itself will progress after infection with COVID-19 in PAP patients is also a point of great interest to us, which requires further follow-up research.