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| ORIGINAL ARTICLE |
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| Year : 2021 | Volume
: 7
| Issue : 2 | Page : 135-141 |
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Clinical course and outcomes of heart transplant patients with COVID infection
Manoj Kumar Sahu1, Seshagiribabu Yagani1, Prateek Vaswani1, Prashant Sirohiya2, Sarvesh Pal Singh1, Milind Padmakar Hote1, Sandeep Seth3
1 Department of Cardiothoracic and Vascular Surgery, Cardiothoracic Centre, All India Institute of Medical Sciences, New Delhi, India
2 Department of Onco-anesthesia and Palliative Medicine, NCI (Jhajhar), All India Institute of Medical Sciences, New Delhi, India
3 Department of Cardiology, Cardiothoracic Centre, All India Institute of Medical Sciences, New Delhi, India
| Date of Submission | 24-Apr-2021 |
| Date of Decision | 30-Jun-2021 |
| Date of Acceptance | 09-Jul-2021 |
| Date of Web Publication | 31-Aug-2021 |
Correspondence Address:
Manoj Kumar Sahu
Department of Cardiothoracic and Vascular Surgery, Room No. 5, 7th Floor, Cardiothoracic and Neurosciences Centre, All India Institute of Medical Sciences, New Delhi - 110 029
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jpcs.jpcs_24_21
Objective: The objective is to assess the clinical course and outcomes of heart transplant (HTx) recipients affected by COVID-19 disease in a tertiary care health care institution. Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is a contagious illness with alarming morbidity and mortality. The HTx recipients are chronically immunosuppressed and thus COVID-19 infection in them may result in an unpredictable clinical course. Materials and Methods: HTx recipients in a tertiary care transplant center in North India were retrospectively reviewed from January 2020 to January 2021. Case records of 28 patients of HTx were reviewed, and four (14%) were found to have developed Covid-19 infection. Clinical parameters and outcomes of these four HTx recipients with confirmed SARS-CoV-2 infection are described. Results: Fourteen percent of our HTx patients (4 out of 28 patients under follow-up) developed COVID-19 in the first infection wave. The study population consisted of 3 males and 1 female patient with a median age of 28 years (range 15–39). The most common presenting symptoms were fever (100%), myalgia (100%) and cough (75%). There was no mortality observed in this study. None required intensive care admission or mechanical ventilatory support. Three were managed with hospital admission while one was subjected to home isolation. The mean hospital stay was 13.5 days (12–17 days). Immunosuppressants were modified by reducing tacrolimus and mycophenolate, however, corticosteroids were continued. Conclusion: The dose modification rather than discontinuation of immunomodulatory agents should be established as standard of care for transplant recipients. Steroids may provide added benefit and should be continued. The morbidity and mortality in such cases may be lower than anticipated; however, this needs to be substantiated with larger multicentric studies.
Keywords: Heart transplant patients, immunosuppressants, intensive care unit admission, severe acute respiratory syndrome coronavirus 2 infection
How to cite this article:
Sahu MK, Yagani S, Vaswani P, Sirohiya P, Singh SP, Hote MP, Seth S. Clinical course and outcomes of heart transplant patients with COVID infection. J Pract Cardiovasc Sci 2021;7:135-41 |
How to cite this URL:
Sahu MK, Yagani S, Vaswani P, Sirohiya P, Singh SP, Hote MP, Seth S. Clinical course and outcomes of heart transplant patients with COVID infection. J Pract Cardiovasc Sci [serial online] 2021 [cited 2023 Jun 8];7:135-41. Available from: https://www.j-pcs.org/text.asp?2021/7/2/135/325222 |
| Introduction | |  |
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan province, China in December 2019 and quickly spanned worldwide in a short span of time.[1] The first SARS-CoV-2 positive case in India was reported in the state of Kerala on January 30th, 2020.[2] Subsequently, the number of cases drastically rose in all parts of the country. The resulting demise of routine health care provision and declining standard of health care provision affected all specialties. This pandemic posed certain specific challenges in the post-transplant patients. The heart transplant (HTx) recipient follow-up has been shaken to its roots without any evidence-based guidelines in managing those afflicted by this virus.
The HTx recipients are chronically on immunosuppressant medications which modify their immunity and defensive response against various pathogens. The imminent threat to these patients in the face of pandemic remains fierce. The leading cause of mortality in HTx patients includes primary graft dysfunction/failure, allograft rejections and secondary super-added infections which may be either bacterial, viral or fungal in origin.
These HTx recipients usually are on triple-drug immunosuppressive therapy consisting of calcineurin inhibitors such as tacrolimus or cyclosporine, antimetabolites or purine synthesis inhibitors such as mycophenolate mofetil (MMF) and corticosteroids. The added medical comorbidities such as hypertension, diabetes and chronic renal failure may add to the mortality risk.
The available literature on this subject hypothesize that this subset forms a unique epidemiological cohort which may remain protected from abnormal host response resulting due to the cytokine surge.[3],[4] The lack of a standard management strategy and unclear course in such patients mandates the follow up of post HTx patients afflicted with COVID-19.[5] The mortality in such patients may vary from 2% to 15% and with further addition by the comorbidities.[6],[7] Hence, in this study, we aim to describe our experience in this regard.
| Materials and Methods | | |
We retrospectively reviewed 28 HTx patients at our center from January 2020 to January 2021. In the face of COVID 19 pandemic, the routine physical follow-up visits were suspended and telephonic consultations were carried out. Suspected individuals were subjected to reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of nasopharyngeal specimen (NPS). Four cases with confirmed laboratory evidence of SARS-CoV-2 were included in the study. They were categorized into one of the three groups according to a previously reported clinical severity scale-mild (hospitalization not required), moderate (hospitalization) required and severe disease (hospitalization plus need for intensive care unit [ICU] admission, mechanical ventilation [MV] or mortality).[8],[9]
The history, clinical parameters, medications, hospital stay and final outcomes were obtained. Statistical analysis-Continuous variables are expressed as median and range, categorical variables are presented as frequency and percentage. All statistical analyses were performed using SPSS software version 20 (IBM SPSS Statistics, IBM Corp., Armonk, NY, USA).
The study was approved by our Institute Ethics Committee. Formal consent was not required for this retrospective data review.
| Results | | |
Patient demographics
From January 2020 to January 2021, four out of 28 HTx recipients (14%) in our institute program, had confirmed SARS-CoV-2 infection and all developed mild to moderate COVID-19 illness. The median age of these four COVID 19-infected patients was 28 years (range of 15–39) and three of them were males (75%). The median time from transplant was 3.9 years (2.9–20 years).
The most common presenting symptoms for COVID 19 in HTx recipients were fever (100%), myalgia (100%) and cough (75%). This was followed by headache, sore throat and anosmia which were reported in 50% of cases. None of our patients presented with gastro-intestinal or cardiovascular symptoms. The patient demography and symptomatology are described in [Table 1]. | Table 1: Demographic, clinical and laboratory data of the COVID-19 infected heart transplant patients
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Two of the infected HTx patients had a history of exposure to a family member with COVID 19 and rest were residing in hot spot areas.
Two patients (HTx recipients 2, 3) presented with increased respiratory rate and lower oxygen saturation with pulse oximeter on room air <92%. The vital parameters including oxygen saturation are delineated in [Table 2]. Three out of the four patients required hospital admission. One patient was managed with home isolation care and telephonic Consultations. She was the longest survivor, transplanted 20 years before in our cohort of HTx recipients. None of the patients required ICU admission or need of invasive MV. | Table 2: Hemodynamic and respiratory parameters of COVID affected heart transplant patients on admission day
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Laboratory data
All patients had elevated C-reactive protein (CRP) with a median peak level 2.7 mg/dl (2.1–3.9) on admission and 1.34 mg/dl (1.0–2.1) on day 5 after admission. Other inflammatory markers such as procalcitonin (median = 0.01 and 0.015 ng/ml), IL-6 (1.65 and 1.95 pg/dl) and ferritin (55 and 49.35 ng/dl) were within normal range in all patients on admission and 5th day after admission, respectively. Two HTx recipients (HTx 2 and 3) had mildly elevated D-dimer levels on admission day (679 ng/ml and 532 ng/ml respectively) but a decline was observed in day 5 levels for both the patients. Fibrinogen (401 mg/dl) and lactate dehydrogenase (LDH) (279 U/L) were elevated in one patient (HTx-4) on admission but decreased on day 5 to 366 mg/dl and 207 U/L respectively. Creatinine phosphokinase also was mildly elevated (311 IU/L) in one patient (HTx 3) on day of admission and decreased to 222 IU/L on 5th day. Hemogram, liver and renal function tests were within normal limits on day of admission and 5th day for all four patients. Lower platelet counts at 1.20 lacs were noted on the admission day which improved up to 1.70 lacs by 5th day in our patients. The hematological, biochemical, inflammatory and coagulation parameters are presented in [Table 1] and [Table 3]. | Table 3: Laboratory inflammatory and coagulation markers on admission and on day 5 after admission
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Treatment
In our study, all three male patients were admitted to isolated single rooms in the designated COVID centre in our institute after laboratory conformation of SARS CoV-2 and received oxygen supplementation with simple facemask at 6 L/min. One female patient was home isolated and did not require oxygen supplementation.
The modifications were done with the maintenance immunosuppressants in all the HTx recipients affected by SARS-CoV-2. MMF was held in all patients (100%) throughout treatment and up to 15 days after discharge from the hospital. Tacrolimus dosage was decreased in all (100%) patients to achieve a lower blood trough level of 6–7 ng/ml. All of them were taking oral prednisone 5 mg daily except the female patient, who was on 2.5 mg/day. The same dosage of corticosteroids was continued throughout the disease. We did not give bolus dose of glucocorticoids nor escalated the dose of the steroids for our patients. Two of our patients-HTx 1 and 2 received ivermectin and azithromycin as they had an exposure history. None of our patients received hydroxychloroquin or remdesivir or tocilizumab or plasma therapy. The fourth patient received azithromycin for 5 days for concern of bacterial superinfection after 7 days hospital stay after confirming the absence of QT prolongation on ECG. All the patients received paracetamol 500 mg, Vitamin C 500 mg, vitamin D3, calcium, zinc and multivitamin B complex supplementation during hospitalization and at discharge. The management of all four COVID-affected HTx recipients is presented in [Table 4]. | Table 4: Management of heart transplant recipients with COVID-19 disease
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Outcomes
All the HTx patients were followed up telephonically with additional video calls throughout the COVID 19 pandemic, except when some important or severe complaints such as dyspnea, pedal edema, fever, diarrhea occurred, the patients were called to the hospital for treatment. The COVID-19 affected patients in our cohort complained of their symptoms telephonically and were advised to observe the temperature chart and take paracetamol if necessary and review once symptoms develop. When the fever, myalgia or other debilitating symptoms did not subside by routine treatment for 48 h, they were called to the hospital emergency, tested for SARS CoV-2, upon which four patients became positive for COVID by RT-PCR test from NPS. Three of the four patients required hospitalization, they were categorized as having moderate disease and one patient did not require hospital admission and categorized as mild disease. One patient (HTx 2) was found to have some mild infiltrations on chest X-ray, but other three patients did not have any radiological evidence of lung lesions. The three were admitted to the COVID designated area in single isolated rooms. Average length of stay for the hospitalized patients was 13.4 days with a range of 10-17 days. No patient in our cohort required ICU admission or MV either invasive or non-invasive. None of our patients had comorbidities like diabetics, hypertension, chronic obstructive pulmonary diseases, chronic kidney diseases. One female patient who was treated as outpatient with strict home isolation had moderate left ventricular dysfunction on echocardiography. All patients discharged as per our institutional protocol when they were asymptomatic, without oxygen support for more than 48 h with two RT-PCR tests done 24 h apart depicting negative COVID-19 status.
One patient (HTx-2) continued to have a positive RT-PCR test for COVID-19 from NPS two times after cessation of clinical symptoms. He was subjected to another RTPCR test 48 h later, which came negative, thereby having the longest hospital stay of 17 days. This patient came back after 3 weeks with diarrhea and was dehydrated on presentation with impaired renal parameters. The patient was COVID-19 negative on RT-PCR testing and recovered well with intravenous fluids and metronidazole. The other two patients did not require readmission and were asymptomatic on 30 and 90 days' follow-up.
| Discussion | | |
The HTx surgeries are routinely performed in our institution. All the HTx recipients under physical follow-up at our institute on regular basis twice weekly on Tuesdays and Fridays physically at a particular interval for the individual recipients depending on their duration of transplantation, which ranges from every 15 days in the 1st 3 months and then one monthly in the rest of the 1st year and then every 3 monthly from 2nd year onwards. However, during this coronavirus pandemic starting from march 2020 till February 2021, physical hospital visits were restricted and more telephonic follow-ups were carried out except for those developed complaints such as fever, vomiting, diarrhea, severe pain in limb, back, chest, headache etc., those were called for direct physical examination in the follow-up HTx clinic in our centre. Patients after HTx represent a particularly vulnerable group to SARS CoV-2 infection due to chronic immunosuppression, high rates of comorbidities and frequent contacts with medical professionals.
Three of our HTx recipients were young adults aged >18 years and the fourth one was a child of 15 years of age. All of them had moderate COVID 19 symptoms except one who had mild features on presentation. All of them convalesced to recovery with standard practice of COVID management for moderate disease and adjustment of immunosuppression medication and none of them deteriorated to severe category. One female patient who is the longest HTx survival in our cohort was symptomatic in the form of fever, myalgia, anosmia and she was isolated at home with adjustment of immunosuppressants and standard prophylaxis with ivermectin and azithromycin. Our study result was comparable with the study by Latif et al., the authors showed a higher rate of COVID-19 infection among male patients.[10] Interestingly, the above mentioned female patient in our cohort did not require hospitalization as she smoothly convalesced from the COVID-19 disease. The same study also reported the case-fatality rate of HTx recipients with COVID-19 infection was at 25% and many other studies in literature showed the case fatality rate ranging from 2% to 15% according to different regions of the globe and it might rise with added comorbidities.[6],[7] The authors in these studies have stated that majority of patients had moderate to severe disease and the disease severity could have contributed to the additional mortality observed.[6],[7],[10] In contrast, there was no mortality in our study cohort as none of them developed severe intensity of COVID infection. Furthermore, none of them had debilitating medical comorbidities. In contrast, the patients in the group by authors Latif et al. were elderly and had multiple comorbidities.[10] None of our patients required ICU admission, MV and all of them recovered before discharge. This could have resulted from continuation of steroids which has probably been responsible for counteracting the initial cytokine storm. The authors Yin et al. in their study stated that the addition of corticosteroids may be justified in severe forms to alleviate disastrous pulmonary parenchymal damage.[11] Second, the steroids may reduce risk of immune reactions preventing graft failure.[11]
Thus, HTx recipients pose an unpredictable course when infected by SARS-CoV-2, they may become more vulnerable to the COVID infection and its complications or on the other hand, they may get protected from the aggressive cytokine storm because of immunomodulation by continued corticosteroid therapy resulting in better recovery.
Three out of four patients (HTx 1-3) had neutropenia and all had isolated mild thrombocytopenia without any bleeding tendencies at the time of presentation but improved to normal by 5th day except in one patient who continued to have neutropenia with thrombocytopenia. This patient was the one who had the longest hospital stay (HTx 2), however, this finding cannot be standardized as predominantly the post-transplant patients on chronic immunosuppressants (antimetabolites in particular) can become neutropenic. The other two hospitalized recipients also showed leucopenia on admission day which was observed to be normal on 5th day. Thrombocytopenia has also been reported by Bhattacharjee and Banerjee in their study.[12] None of our patients had lymphopenia which differentiates our study from others. The only inflammatory maker which was mildly elevated in all patients on admission and decreased to normalcy by 5th day was CRP. Other inflammatory parameters were normal in our group of COVID-infected patients, in contrast to other studies, those documented a significant rise in different inflammatory markers, which could have resulted in higher morbidity and mortality.[13],[14]
Immunosupressant management
Chronic immunomodulatory agents form the mainstay of therapy for recipients of HTx which include calcineurin inhibitors in combination with inhibitors of purine synthesis. The therapeutic action consists of deactivation of lymphocytic response which is also responsible for viral infectious pathophysiology. The lack of evidence-based guidelines for the management of transplant recipients prevents a standardized management protocol. However, similar to the other viral pathologies affecting transplant patients, the reduction of immunomodulatory agents formed our first response. This basis is strengthened by the leucopenia usually observed with COVID-19 infections similar to other forms of viral illnesses.
The authors Gandolfini et al.[15] and Zhu et al.[16] studied the interaction of COVID-19 infection in renal transplant patients, where complete interruption of immune therapy was allocated for management. However, suspension of all agents could adversely result in catastrophic sequelae of graft dysfunction and immune reactions potentially being fatal in association with COVID-19 related inflammatory overdrive. In addition to this, whether the anti-inflammatory response of long-standing immune-modulatory drugs play a role in the “cascade of cellular demise” brought on by the cytokine release and activated leukocyte-monocytic association is not substantiated by evidence.[8],[17]
The pulmonary sequelae are a result of overstimulation of immune response rather than viral illness, hence, completely suspending the immune-modulatory agents may not be justified.[18]
The drug reactions based on inhibition of enzymatic pathways may result in increasing serum levels of immune-suppressive agents; therefore, a reduction of dosage should be adopted as we also did.
Current guidelines from experts recommend considering temporary withholding the MMF, mammalian target of rapamycin inhibitors (e.g., sirolimus/everolimus) in cases of moderate/severe COVID-19 infection.[19] Decker et al. found that immunosuppressants were either totally discontinued or partial reduction in dose was done in 71.8% of patients.[20] The MMF was withheld in all our patients in total duration of hospitalization and it was restarted two weeks after the patients become RT-PCR negative for SARS CoV-2 infection. We also decreased the dose of tacrolimus for the duration of illness in all our patients and kept their blood trough levels lower at around 6–7 ng/ml. We continued the prednisolone at the same dose as they were receiving before, three patients were on 5 mg/day, whereas one patient was on 2.5 mg/day. We did not need to increase the steroid dose nor required to give bolus higher dose because all four of our patients did not have disease deterioration clinically or laboratory biomarker-wise and they improved gradually.
Treatment of COVID-19 infection
Two of our infected patients (one with home isolation and one admitted patient having lower O2 saturation) received Azithromycin and Ivermectin. The other two patients among the three admitted patients were not given any repurposed drugs. All four patients received the adjunct therapy such as Vitamin D, Vitamin C, and zinc. In contrast to our study, some other study population received higher dose of steroids and remdesivir for moderate to severe infection, admitted to ICU and were on MV.[21],[22]
Few studies reported HTx recipients with COVID-19 disease had a longer period of hospital stay[23],[24] but none of our patients required hospital stay more than 3 weeks, this could be due to younger age group, strict isolation in single bed cubicles even if they had mild-to-moderate form of disease and maintaining meticulous personal hygiene and sterility of the care area, severe restriction of visitors, all these measures prevented secondary bacterial or fungal infections which prevented further aggravation of the disease. Apart from this, chronic prednisolone therapy might have offered protection from further progression of the disease to severe state, but this is an assumption, need to prove by multicentric studies. Another very important aspect is, we promptly asked the patients to get admitted to the hospital as their symptoms did not subside within 48 h, and we treated three of our patients with repurposed drugs along with the recommended modification with the immunosuppressants. All these steps together helped our patients preventing the disease progression and development of cytokine storm.
The standard of care provided is definitely affected in the pandemic times and the level of care demanded in these special transplant recipients is challenged. The overall mortality in this subset may also be lowered by the proper distance maintenance and strict adherence to hand hygiene and wearing layered masks as a part of routine follow-up.
Limitations
This is a single-center study, hence, the findings may be affected by institution-specific variables and cannot be generalized to the population at large. It may not reflect the epidemiology of different centers and/or geographical areas, thus more extensive data are needed to confirm these findings. The small sample size of this study cannot exclude a type 2 error. The lacunae still exist in corroboration of clinical scenario with biochemical parameters which may help to modify immune-modulatory therapy in transplant individuals.
| Conclusion | | |
The clinical course of SARS-CoV-2 infection in HTx recipients appeared to be similar to that observed in the non-transplant population. This cohort reflected predominantly mild-moderate disease severity and was managed with only symptomatic treatment along with modification of long-term immunosuppression regimes and oral steroid therapy. The small study cohort proved that the impact of modification of immunosuppressant drugs is indeed helpful. We suggest an early RT-PCR testing after symptoms and admission to isolated single bed cubicles in the hospitals, however, this may be affected in pandemic crisis. The clinical picture should guide the treatment strategy till an evidence-based guideline is ensued.
Ethics clearance
Ref no. IEC-201/09.04.2021, Approved by Institute Ethics Committee, AIIMS, New Delhi.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]
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