Abstract
Background
Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic has been raging since the end of 2019 and has shown worse outcomes in solid organ transplant (SOT) recipients. The clinical differences as well as outcomes between respiratory viruses have not been well defined in this population.
Methods
This is a retrospective cohort study of adult SOT recipients with nasopharyngeal swab or bronchoalveolar lavage PCR positive for either SARS‐CoV‐2, seasonal coronavirus, respiratory syncytial virus (RSV) or influenza virus from January 2017 to October 2020. The follow up period was 3 months. Clinical characteristics and outcomes were evaluated.
Results
A total of 377 recipients including 157 SARS‐CoV‐2, 70 seasonal coronavirus, 50 RSV and 100 influenza infections were identified. The most common transplanted organ was kidney 224/377 (59.4%). Lower respiratory tract infection (LRTI) was found in 210/377 (55.7%) and the risk factors identified with multivariable analysis were SARS‐CoV‐2 infection, steroid use, and older age. Co‐ and secondary infections were seen in 77/377 (20.4%) recipients with bacterial pathogens as dominant. Hospital admission was seen in 266/377 (67.7%) recipients without significant statistical difference among viruses, however, ICU admission, mechanical ventilation and mortality were higher with SARS‐CoV‐2 infection. In the multivariable model, the risk factors for mortality were SARS‐CoV‐2 infection and older age.
Conclusions
We found higher incidence of ICU admission, mechanical ventilation, and mortality among SARS‐CoV‐2 infected recipients. Older age was found to be the risk factor for lower respiratory tract infection and mortality for SARS‐CoV‐2, coronaviruses, RSV and influenza virus groups.
Keywords: SARS‐CoV‐2, coronavirus, influenza, solid organ transplant recipients
Abbreviations
- (ALC)
Absolute lymphocyte counts
- (CNI)
Calcineurin inhibitor
- (COVID‐19)
Coronavirus disease
- (ICU)
Intensive care unit
- (LRTI)
Lower respiratory tract infection
- (MERS)
Middle East respiratory syndrome
- (RSV)
Respiratory Syncytial virus
- (SARS)
Severe acute respiratory syndrome
- (SARS‐CoV‐2)
Severe acute respiratory syndrome coronavirus 2
- (SOT)
Solid organ transplant
- [IQR]
Interquartile range
1. INTRODUCTION
As of 28 August of 2022, the World Health Organization had reported more than 598 million people infected with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and more than 6.4 million cumulative deaths. 1 There are many established risk factors for severe illness and mortality from coronavirus disease (COVID‐19) and one important factor is solid organ transplantation (SOT). 2 , 3
SOT recipients are more likely to develop severe disease as compared to the general population when infected with respiratory viruses, including influenza. 4 , 5 , 6 This may be because SOT recipients are unable to mount a robust immunity against those organisms, especially due to the fragile T‐cell mediated immune response. 7 Influenza viral infection in SOT recipients has been better studied as compared to other respiratory viral infections. 4 However, there is a paucity of data regarding other respiratory viral infections among SOT recipients. The clinical data regarding seasonal coronavirus infections in SOT recipients are even scarcer.
SARS‐CoV‐2, which belongs to the coronavirus group, is not the first pandemic in history. In the last 100 years, there have been several influenza and other coronavirus pandemics, including Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS), which were reported in the year of 2012 and 2002, respectively. 8 The COVID‐19 pandemic, which has been raging since the end of 2019, has also significantly affected SOT recipients and several reports showed significantly worse outcomes in SOT recipients with COVID‐19. 9
During the pandemic, there has been a question of worse outcomes with SARS‐COV‐2 compared to other “better known” respiratory viruses such as influenza 10 , 11 , 12 or respiratory syncytial virus (RSV).
There is a lack of data showing the differences and similarities in clinical presentation, laboratory findings and outcomes in SOT recipients. 13 In this study, we conducted a comparison of clinical presentation and outcomes in SOT recipients infected with SARS‐COV‐2, seasonal coronaviruses, RSV and influenza virus.
2. METHODS
2.1. Study design
This is a single center retrospective cohort study, conducted at Miami Transplant Institute, Jackson Health System, Florida, USA. Miami Transplant Institute is one of the biggest SOT centers in North America and performs more than 600 organ transplants annually. Miami Transplant Institute also provides the comprehensive follow up for transplanted recipients. We included adult SOT recipients with reverse transcription polymerase chain reaction (PCR)‐confirmed SARS‐CoV‐2, seasonal coronavirus (including COVHKU1, COV229E, CoVNL63, CoVOC43), RSV and influenza virus infection (influenza A and B). Potential participants were identified through our electronic medical record. We have also maintained the database for SOT recipients with COVID‐19. We included recipients whose age were more than and equal to 18 years at the time of diagnosis. We excluded patients without an active allograft at the time of diagnosis of respiratory viral infection. These infections were diagnosed from January 2017 to October 2020. Of note, in our institution, since June 2020, all admitted patients required screening PCR testing, regardless of the symptoms for COVID‐19. We have not implemented such kind of screening testing for influenza, RSV or seasonal coronaviruses. We would like to highlight that for patients diagnosed with SARS‐CoV‐2 infection, during the study period, we reduced mycophenolate mofetil at least 50% per institutional protocol. The study was approved by our Institutional Review Board (IRB # 20150360) and conducted consistently with principles in the Declaration of Helsinki. Informed consent was exempted by the IRB due to the retrospective nature of this study.
2.2. Diagnosis for respiratory viral infections
The diagnosis was made based on PCR positivity of either nasopharyngeal swabs and/or bronchoalveolar lavage specimens. The PCR platform used for influenza and RSV was Cepheid Infinity. For seasonal coronavirus, we used the BioFire platform. For SARS‐CoV‐2, the majority of patients diagnosed in our institute were using Cepheid SARS CoV‐2/Flu/RSV RT‐PCR. However, we also included patients diagnosed in outside institutions where they used different platforms, however, those recipients had a confirmatory test on admission to our hospital. For the purpose of analysis, we only included the first episode of each unique virus. Each new community acquired respiratory virus episode was included in the analysis as a unique episode.
2.3. Variables
We collected demographic data including age as a continuous variable, as well as symptoms, laboratory, and radiological findings on presentation. The primary outcome of this study was mortality. The follow‐up period for all variables was 3 months after diagnosis. As a secondary outcome, we collected hospital admission, co‐ and secondary infections, intensive care unit (ICU) admission, mechanical ventilation, and rejection. We also calculated the neutrophil/lymphocyte ratio. 14 Lower respiratory tract infection (LRTI) was defined as the presence of radiological abnormalities on either a chest radiogram or CT scan. 15 Rejection was defined as any pathology findings concerning for acute rejection on an allograft biopsy. Co‐ and Secondary infections were defined as any culture or PCR positivity obtained at the day of diagnosis and within 90 days after diagnosis of the respiratory viral infection, respectively; no serologic or other markers were used for this diagnosis. For secondary infection, other than respiratory specimens, the positivity of only sterile specimens including blood, cerebral spinal fluid and non‐sterile such as urine, were considered as infection. For urine culture positivity, the presence of urinary tract symptoms should also be required. For non‐sterile culture, such as respiratory specimens, culture positivity along with compatible symptoms and/or radiological changes should have been present. For invasive fungal disease (IFD) diagnosis, we used the European organization for research and treatment of cancer (EORTC) definitions and we included probable and proven IFDs. 16
2.4. Statistical analyses
Demographic, medical, and treatment characteristics were summarized using descriptive statistics. For categorical variables, we conducted a chi squared test or fisher's exact test, whichever appropriate. A post hoc analysis was conducted on a Z test with Bonferroni method. Either Mann Whitney U‐test or one way ANOVA was applied for continuous variables. As a post hoc analysis after one way ANOVA, Turkey test was conducted when needed. For time to event analysis, we performed a log‐rank test. We also developed a multivariable model to determine the risk factors for mortality and developing LRTI. For multivariable analysis, logistic regression model with stepwise backward elimination was developed and variables whose p values less than 0.2 with univariate analysis were put into the multivariable model, after checking correlations between variables. All tests were two‐sided, and P value of less than 0.05 was considered of statistical significance.
3. RESULTS
3.1. Demographics
Between January 2017 to October 2020, a total of 377 SOT recipients were identified. This included 157 SARS‐CoV‐2, 70 seasonal coronavirus, 50 RSV, and 100 influenza infected recipients. Detailed demographics including immunosuppression are summarized in Table 1. In short, 40.8%, 47.1%, 58.0% and 43.0% were female in SARS‐CoV‐2, seasonal coronavirus, RSV and influenza virus, respectively. Among 377 recipients, the median age and time from transplant to diagnosis were 54 (Interquartile range [IQR] 43–64) years old and 23.57 (IQR 7–67) months, respectively. The most common organ transplanted was kidney in 71.9%, 38.6%, 52.0% and 58.0% in SARS‐CoV‐2, seasonal coronavirus, RSV and influenza virus, respectively. Maintenance immunosuppression prior respiratory virus diagnosis including calcineurin inhibitors, antimetabolites and prednisone were given in 84.4%, 77.5%, and 57.0%, respectively, among 377 patients. Unfortunately, we do not have data on prior influenza vaccination in our cohort.
TABLE 1.
Characteristics and clinical presentation of solid organ transplant recipients with SARS‐CoV‐2, seasonal coronavirus, RSV and influenza infection
| SARS‐COV‐2 (n = 157) | Seasonal (n = 70) | RSV (n = 50) | Influenza (n = 100) | p‐Value | |
|---|---|---|---|---|---|
| Gender (female) | 64 (40.8%) | 33 (47.1%) | 29 (58%) | 43 (43.0%) | 0.18 |
| Age (years) | 55 (46 – 63) | 60 (42.25 – 66) | 59 (44 – 68) | 49.5 (39‐62) | 0.20 |
| Transplanted organ | |||||
| Kidney transplant | 113 (71.9%) | 27 (38.6%) | 26 (52%) | 58 (58.0%) | <0.001 |
| Liver transplant | 15 (9.6%) | 4 (5.7%) | 7 (14%) | 10 (10.0%) | 0.5 |
| Lung transplant | 3 (1.9%) | 20 (28.6%) | 8 (16%) | 6 (6.0%) | <0.001 |
| Heart transplant | 12 (7.6%) | 9 (12.8%) | 3 (6%) | 13 (13.0%) | 0.316 |
| Other/combined | 14 (8.9%) | 10 (14.3%) | 6 (12%) | 13 (13.0%) | 0.614 |
| ATG within 6 months as part induction | 29 (18.5%) | 14 (30.0%) | 3 (6%) | 19 (19%) | 0.159 |
| Maintenance Immunosuppression | |||||
| Prednisone | 94 (59.8%) | 43 (61.4%) | 29 (58%) | 49 (49.0%) | 0.08 |
| Calcineurin inhibitor | 130 (82.8%) | 60 (85.7%) | 42 (84%) | 86 (86.0%) | 0.83 |
| Antimetabolites | 131 (83.4%) | 46 (65.7%) | 37 (74%) | 78 (78.0%) | 0.005 |
| Laboratory findings | |||||
| ANC (103 cells/μL) | 3.7 (2.4 – 6.1) | 4.6 (3.5 – 7.3) | 3.9 (3.5 – 8.4) | 4.3 (3 – 6.7) | <0.001 |
| ALC (103 cells/μL) | 0.7 (0.4 – 1.2) | 0.7 (0.4 – 1.2) | 0.5 (0.3 – 1.1) | 0.6 (0.3–1.2) | 0.37 |
| Time to infection post‐ SOT (months) | 25 (7.8 – 73) | 14.25 (6 – 40.5) | 14.35 (3.9 – 45) | 33 (9.4 – 90) | <0.001 |
| Symptoms at presentation | |||||
| Fever | 63 (40.1%) | 18 (25.7%) | 12 (24%) | 72 (72%) | <0.001 |
| Cough | 69 (44%) | 36 (52.4%) | 30 (60%) | 69 (69%) | <0.001 |
| Shortness of breath | 65 (41.4%) | 13 (18.6%) | 19 (38%) | 21 (21%) | <0.001 |
| Diarrhea | 32 (20.4%) | 3 (4.3%) | 3 (6%) | 16 (16%) | 0.01 |
| Nausea/vomit | 14 (8.9%) | 8 (11.4%) | 5 (10%) | 14 (14%) | |
| Abdominal pain | 8 (5.1%) | 3 (4.3%) | 1 (2%) | 4 (4%) | 0.82 |
| Chest pain | 12 (7.6%) | 3 (4.3%) | 1 (2%) | 3 (3%) | 0.43 |
| Asymptomatic | 27 (17.2%) | 7 (10%) | 0 | 3 (3%) | <0.001 |
Abbreviations: ALC, Absolute lymphocyte count; ANC, Absolute neutrophil count; ATG, anti‐thymocyte globulin.
3.2. Clinical presentation
Details of symptoms are shown in Table 1. Fever was present in 40.1%, 25.7%, 24.0% and 72.0% in SARS‐CoV‐2, seasonal coronavirus, RSV, and influenza virus, respectively with a statistically significant difference (p < 0.001) among these viruses with higher fever episodes seen in influenza. Also, cough was seen in 44.0%, 52.4%, 60.0% and 69.0% in SARS‐CoV‐2, seasonal coronavirus, RSV, and influenza virus, respectively with a statistically significant difference (p < 0.001), again higher presence in patients with influenza. Any gastrointestinal symptoms including diarrhea, nausea and abdominal pain were found in 30.2% of all recipients. Of note, abdominal symptoms were less likely to be seen in seasonal coronavirus group after post hoc analysis (p = 0.012). We also recorded asymptomatic patients, 17.2%, 10.0%, 0% and 3.0% in SARS‐CoV‐2, seasonal coronavirus, RSV and influenza virus groups, respectively.
3.3. Laboratory data and imaging
The median values of absolute neutrophil cell counts (ANC) were 3,700 (IQR 2,400 ‐ 6,100) cells/μL, 4,600 (IQR 3,500 ‐ 7,300) cells/μL, 3,900 (IQR 3,500 – 8,400) cells/μL and 4,300 (IQR 3,000 ‐ 6,700) cells/μL for SARS‐CoV‐2, seasonal coronavirus, RSV and influenza virus, respectively. COVID had statistically different ANC with coronavirus, RSV and Influenza (p = 0.005, 0.001, and 0.016, respectively). The median value of absolute lymphocyte counts (ALC) was 700 (IQR 400 ‐ 1,200) cells/μL, 700 (IQR 400 ‐ 1,200) cells/μL, 500 (IQR 300 – 1,100) cells/μL and 600 (IQR 300 ‐ 1,200) cells/μL for SARS‐CoV‐2, seasonal coronavirus, RSV and influenza virus, respectively. There were no statistically significant differences among groups for lymphocyte count (p = 0.37). The median neutrophil/lymphocyte ratios were 4.4 (IQR 2.6 ‐ 10.2), 5.7 (IQR 2.8 ‐ 13.8), 7.7 (IQR 4.2 – 19.5), 8.4 (IQR 3.5 ‐ 19) for SARS‐CoV‐2, seasonal, RSV and influenza, respectively, without having a statistically significant difference (p = 0.56).
Chest radiogram and/or CT chest were obtained in 330/377 (87.5%) patients. LRTI was found in 210/330 (63.6%). Of note, LRTI was found 103/130 (79.2%), 36/58 (62.1%), 26/47 (55.3%) and 45/95 (47.4%) for SARS‐CoV‐2, seasonal coronavirus, and influenza virus, respectively. Development of LRTI was higher in SARS‐CoV‐2 as compared to the other three viruses (p<0.001) after post‐hoc analysis.
3.4. Co‐ and secondary infections
Laboratory confirmed co‐ and secondary infections occurred in 41/157 (26.1%), 14/70 (20.0%), 2/50 (4.0%) and 19/100 (19.0%) for SARS‐CoV‐2, seasonal coronavirus, RSV and influenza virus, respectively. Details of secondary infections were summarized in Table 2. Co‐infections, diagnosed on the same day as the viral infection, were found in 22/76 (28.9%) recipients. The median duration between the respiratory viral infection and development of secondary infection was 7 (3‐16) days; in the case of SARS‐CoV‐2, it was 12.5 (IQR 4–18.5) days. Of note, proven and probable pulmonary Aspergillosis were found in 5, 4, 1 and 2 patients in SARS‐CoV‐2, seasonal coronavirus, RSV and influenza virus, respectively. Also, there were 2 patients with fusarium bloodstream infection after SARS‐CoV‐2 infection. Out of 76 secondary infections, 24 were pulmonary infections, 12 in the SARS‐CoV‐2 group and 12 in the other viruses. Median time from COVID‐19 diagnosis to mold infection among 12 patients were 6 (IQR 3.5 ‐ 19) days. Concurrent cytomegalovirus viremia was found in 14 (4.3%) recipients with a median of 6.5 days after diagnosis. After post‐hoc analysis, secondary infection was more likely to be seen in SARS‐CoV‐2 compared to RSV(p = 0.009).
TABLE 2.
Co‐infections and secondary infections
| SARS‐COV‐2 (n = 157) | Seasonal (n = 70) | RSV (n = 50) | Influenza (n = 100) | |
|---|---|---|---|---|
| Bacterial infections | 40 | 3 | 1 | 19 |
| GN bacteria | 22 | 3 | 0 | 15 |
| GP bacteria | 25 | 0 | 1 | 3 (Nocardia) |
| C. difficile colitis | 1 | 0 | 0 | 1 |
| Fungal infections | 10 | 5 | 2 | 3 |
| Aspergillus spp | 5 | 4 | 1 | 2 |
| Candida fungemia | 2 | 1 | 0 | 1 |
| Fusarium | 2 | 0 | 0 | 0 |
| P. jiroveci | 0 | 0 | 1 | 0 |
| Viral infections | 7 | 6 | 0 | 5 |
| CMV | 5 | 6 | 0 | 3 |
| Other | 2 (parvo/HSV encephalitis) | 0 | 0 | 2 (EBV, BK) |
| Mycobacterium | 0 | 0 | 0 | 1 |
Abbreviations: BK, BK virus; CMV, cytomegalovirus; EBV, Epstein Barr virus; GN, Gram negative; GP, Gram positive; HSV, herpes simplex virus.
Some patients may have a combination of secondary infections.
3.5. Clinical outcomes
Details of clinical outcomes are shown in Table 3 . Hospital admission was required in 263/377 (69.7%). There was a statistical difference in admission between COVID and non‐COVID coronavirus, p<0.001, however, there was no statistically significant difference between COVID and influenza or RSV. ICU admission was required in 44/157 (28.0%), 10/70 (14.3%), 5/50 (10.0%) and 7/100 (7.0%) after SARS‐CoV2, seasonal coronavirus, RSV and influenza viral infection, respectively. When compared, ICU admission was higher with SARS‐CoV‐2 infection (p<0.001) compared to the other respiratory viruses.
TABLE 3.
Outcomes in solid organ transplant recipients with SARS‐CoV‐2, seasonal coronavirus, RSV, and influenza infection
| SARS‐COV‐2 N = 157 | Seasonal N = 70 | RSV N = 50 | Influenza N = 100 | |
|---|---|---|---|---|
| LRTI | 103/130 (79.2%) | 36/58 (62.1%) | 26/47 (55.3%) | 45/95 (47.4%) |
| Hospitalized* | 128 (81.5%) | 30 (42.8%) | 34 (68.0%) | 71 (71%) |
| ICU admission | 44 (28.0%) | 9 (12.8%) | 5 (10.0%) | 7 (7.0%) |
| Mechanical ventilation | 25 (15.9%) | 3 (4.3%) | 2 (4.0%) | 6 (6.0%) |
| Secondary infection | 41 (26.11%) | 14 (20.0%) | 3 (6.0%) | 19 (19.0%) |
| Rejection up to 90 days | 7 (4.45%) | 1 (1.43%) | 2 (4.0%) | 6 (6.0%) |
| Mortality at 90 days | 21 (13.4%) | 3 (4.3%) | 1 (2.0%) | 4 (4.0%) |
Abbreviations: ICU, intensive care unit; LRTI, lower respiratory tract infection.
With any respiratory symptom, not included admission for other causes.
Mechanical ventilation was required in 36 patients and was found to be higher in SARS‐CoV‐2 infected recipients as compared to seasonal coronavirus, after post hoc analysis (p = 0.005).
Rejection was found in 16 cases with a median of 9 (IQR 3.5 – 28.5) days after diagnosis of a viral infection, with 7 cases in SARS‐CoV‐2, 1 case in the coronavirus group, 2 cases in RSV and 6 cases in the influenza group. Mortality was statistically significantly higher with SARS‐CoV‐2 infection with univariate analysis (p = 0.006) compared to the other viruses. The Kaplan‐Meier curve is shown in Figure 1. Out of 100 influenza viral infected recipients, 99 (99.0%) received Oseltamivir. In the SARS‐CoV‐2 group, out of 157 recipients, 64 (40.8%), 84 (53.5%), 41 (26.1%), and 12 (7.6%) received remdesivir, high dose steroids, convalescent plasma and received tocilizumab, respectively.
FIGURE 1.
Kaplan‐Meier survival analysis
3.6. Risk factors for lower respiratory tract infection and mortality
Risk factor analysis was conducted for development of LRTI and mortality. At first, univariate analysis was conducted. Steroid usage (p<0.001), virus type (p<0.001) and older age (p = 0.003) were statistically significant risk factors for LRTI.
Multivariate model was developed based on the univariate analysis. We put the variables whose p values were less than 0.2 into the model. After multivariate analysis, statistically significant factors to develop LRTI were older age, steroid usage, and SARS‐CoV‐2 (p = 0.006, 0.002, 0.001 respectively).
We also conducted risk factor analysis for mortality. In univariate analysis, virus type (SAS‐CoV‐2), older age and lower ALC were statistically significant risk factors.
In the multivariable model, older age (p<0.001) and SARS‐CoV‐2 (p = 0.026) were identified as risk factors. Compared to other transplants, kidney transplant recipients had lower mortality (p = 0.013).
4. DISCUSSION
This is a single center retrospective cohort study comparing the clinical characteristics of SARS‐CoV‐2, seasonal coronavirus, RSV and influenza viral infection in SOT recipients. To our knowledge, this is the first study to compare these four pathogens among this population. After comparing the four groups, we found that patients infected with SARS‐CoV‐2 were more likely to develop LRTI with higher rates of mechanical ventilation and mortality. A considerable proportion of the recipients developed co‐ and secondary infections after COVID‐19 including mold infections.
In previous studies, 17 probably due to the diminished immune response to viruses, SOT recipients have not been shown to always develop symptoms. In our cohort, cough and fever were the most common symptoms among these four infections; however, the absence of those symptoms cannot exclude the possibility of these respiratory infections. Interestingly, we found that there was a statistical difference in the presence of cough and fever, with higher numbers in the influenza group.
We did not find a significant difference among groups regarding hospitalization. Except between SARS‐CoV‐2 and seasonal coronavirus, however, in this case, it is difficult to really draw a conclusion as there may be a selection bias in the patients who were positive for seasonal coronavirus who needed medical care and maybe there are more patients with this infection in the community who never looked for medical evaluation and for which we do not have any data on. Regarding the other viruses, we found similar hospitalization between SARS‐CoV‐2, RSV and influenza. But, with this data it is difficult to strongly conclude that hospitalization is truly similar. For instance, prior to the current pandemic, patients with respiratory symptoms who might have had influenza, RSV and/or seasonal coronavirus infections, did not always seek medical attention for mild symptoms. Therefore, the threshold of hospital admission for these groups may be different.
The risk factors to develop LRTI have been studied in influenza viral infection in the SOT population, 17 according to Kumar et. al., older age, mycophenolate and 2 or more comorbidities were identified as risk factors for pneumonia development. On the other hand, in our study, we identified older age, steroid (as maintenance immunosuppression) usage, and SARS‐CoV‐2 infection as risk factors for developing LRTI.
Bacterial and fungal secondary infection can be seen in the general population after respiratory viral infection, especially with SARS‐CoV‐2 and influenza viral infection. 18 , 19 Influenza virus has been proposed to alter the structure of the respiratory tract and make it more prone to infections. 20 , 21 , 22 In our cohort, a high secondary infection rate (20.42%) was noted, with a dominance of bacterial infections, which was much higher than in the general population infected with respiratory viral infections. 23 Co‐ and secondary infections after SARS‐CoV‐2 infection have been reported in the transplant population, with bacterial and invasive fungal infections being present in 7.3% and 0.6% respectively. 24 Compared to the study by Kates et. al., our data still showed comparable bacterial infection rate but a little higher fungal, especially mold, co‐infection rate. This still highlights the importance of a high clinical suspicion in these patients when clinical symptoms arise, as co‐infections can affect the clinical outcome of each virus group studied. It is important to highlight that some of these co‐infections may have been the cause of the presentation symptoms, however, it is very difficult to distinguish the true cause; for instance, fever may be a sign of multiple infections.
Previously identified risk factors for high mortality in SOT recipients infected with influenza include unvaccinated status and delayed usage of Oseltamivir. 17 For SARS‐CoV‐2, older age, heart disease, obesity, lung disease and lymphopenia have been identified. 24 , 25 , 26 A recent study comparing the outcomes SARS‐CoV‐2 infection and seasonal influenza reported increased mortality in immunocompromised patients with SARS‐CoV‐2 as compared to seasonal influenza patients, especially among older patients and those with hematological malignancies. 13 In our study, like previous studies, identified risk factors for higher mortality include older age and a lower ALC. We did see higher mortality on the SARS‐CoV‐2 group in the multivariate analysis. Of note, most of the patients in the four groups had lymphopenia without statistical difference. This may be related to either the immunosuppression or secondary to the viral infection itself. 27
There are several limitations in our study. First, for SARS‐CoV‐2 infections, included patients were only up to December 2020, when no monoclonal antibody or vaccines were available. This should affect the recipients’ poorer outcome for SARS‐CoV‐2. Secondly, we could not show the time to negativity of viral PCR. Moreover, especially for seasonal respiratory viral infection, there is no standardized follow up. Third, there may be an intrinsic selection bias, given that in June 2020, our center implemented universal testing for SARS‐CoV‐2 for all recipients who were admitted; this makes the testing threshold different between SARS‐CoV‐2 and respiratory viruses. In the same line, given we are including data from the beginning of the COVID‐19 pandemic, when widespread testing was not available, some of these patients may have had a more severe presentation. Also, given retrospective nature, we may not have been able to identify all the reasons to perform PCR testing in some patients, especially the ones that we defined as asymptomatic.
Something important to mention is that our institutional protocol recommended obtaining a full respiratory viral panel, even during the COVID‐19 pandemic. However, we are aware of the risk of selection bias as there should be a chance of missing cases in this population, especially when they did not develop severe symptoms. Thus, we may have missed some cases.
Due to the retrospective nature of this study, we could not collect the vaccination information especially for influenza. Regarding outcomes based on type of transplant, we couldn't analyze due to the small number of transplants, especially lung, heart and combined transplants. Regarding the evolving treatment recommendations, there has been a significant treatment improvement seen after the study period for COVID‐19 used in our manuscript. As time goes by, we have updated in our institution the treatment protocol including steroid, interleukin 6 inhibitor, supportive care, and usage of remdesivir. On top of that, the changes of variants significantly affected the disease severity. Finally, we only followed 3 months, and based on a recent publication, 28 it may not be enough to capture some complications including secondary infections and rejection.
In summary, this study helps compare the different clinical presentations of these viral infections in the setting of a novel respiratory virus. To our knowledge, this is the first study to compare the mortality and morbidity for the seasonal coronavirus in this vulnerable population. On the other hand, these results highlight the severity of SARS‐CoV‐2 compared to other respiratory infections in terms of ICU admission, mechanical ventilation, and mortality. We believe it is important to show data that proves the difference among these viruses to highlight the worse outcomes in the SARS‐CoV‐2 and to emphasize the importance of preventive measures such as vaccines and monoclonals such as tixagevimab/cilgavimab.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
FUNDING INFORMATION
The authors received no specific funding for this work.
Supporting information
Visual Abstract
Mendoza MA, Motoa G, Raja MA, et al. Difference between SARS‐CoV‐2, seasonal coronavirus, influenza, and respiratory syncytial virus infection in solid organ transplant recipients. Transpl Infect Dis. 2022;e13998. 10.1111/tid.13998
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.