Background: Following partial recovery from acute COVID-19 disease, patients have been reported to suffer from long-term sequelae (beyond 12 weeks from the onset of symptoms), Symptoms vary from mild to life-threatening conditions. This phenomenon is now called post-COVID-19 or long COVID-19. Materials and Methods: Of the total 81 patients with a history of COVID-19, 72 patients were considered for the study. Their clinical data, risk factors, laboratory investigations, radiological findings, management, and outcomes were recorded and statistically interpreted and analyzed. Results: Majority of the patients belonged to the elderly age group. Respiratory symptoms persisted in 53 patients followed by musculoskeletal symptoms seen in approximately 40 patients (55.5%). Renal, neurological manifestations, gastrointestinal, cardiac manifestations, and thromboembolic phenomenon were also seen. Conclusions: In our study, it was concluded that majority of patients presenting with post-COVID-19 sequelae came with persistent respiratory symptoms followed by musculoskeletal and neuropsychiatric manifestations. The repercussions of COVID-19 illness are reverberating and should be managed extensively, as with the rising numbers the burden on health care will also rise. Hence, a need for more research in this field for better diagnosis and management of post COVID-19 syndrome.
Keywords: COVID-19, morbidity, post-COVID syndrome
|How to cite this URL:|
Reddy S, Kamath V, Teli JG, Olakkengil ND, Radhakrishnan B, Markanday K. Study of post COVID-19 sequelae at a tertiary rural health care center. APIK J Int Med [Epub ahead of print] [cited 2022 Sep 25]. Available from: https://www.ajim.in/preprintarticle.asp?id=353255
| Introduction|| |
Around 10% of patients who test positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus remain unwell beyond 3 weeks and a smaller proportion of them for months.,, Persistent post-COVID-19 syndrome, also referred to as long COVID, is defined as symptoms seen usually 3 months after the onset of COVID-19. These symptoms may last for at least 2 months and cannot be explained by another possible diagnosis. It involves persistent physical, medical, and cognitive sequelae, as well as pathological consequences. The pathological consequences may be immunosuppression, and pulmonary, cardiac and vascular fibrosis. The common presentations include fatigue, breathlessness, cognitive dysfunction and others that have an impact on day-to-day activities. The onset may be following initial recovery from an acute COVID-19 episode or symptoms may persist from the initial illness with fluctuations or relapses.,,,, One of the underlying pathological mechanisms being proposed is over expression of transforming growth factor (TGF)-β leading to a protracted state of immunosuppression and fibrosis.,,
The ultimate result of this is increased mortality and depleted quality of life. While acute COVID-19 has been extensively researched, sequelae and post-COVID-19 state have a paucity of material. While the acutely symptomatic patients form the visible tip of the COVID-19 iceberg, the post-COVID-19 sequelae remain in its submerged part, advocating for an absolute need for specialized aftercare.,,,,, Hence, this article concentrates on the manifestations of the post-COVID syndrome that can help in early recognition and management of the same. The general assumption remains that recovery from COVID-19 occurs with the resolution of symptoms and eluding of mortality.,,, There is limited attention given to the early detection and management of potential long-term sequelae, which is perhaps due to the remoteness of certain symptoms from the those of acute infection.
| Materials and Methods|| |
This was a prospective observational study of 72 patients who were admitted at MVJMC and RH, Hoskote, Bangalore, India, from period August 2020 to August 2021. All patients were previously tested positive for the real-time reverse transcription polymerase chain reaction for COVID-19 and presented 3 months post-COVID-19 infection. The COVID status was ascertained from the case records maintained in the hospital and the discharge summaries. The patients were divided as having history of mild, moderate and severe form of disease on the basis of ICMR-Ministry of Health and Family Welfare Guidelines, Government of India 2021, using the oxygen saturation and respiratory rate mentioned in their records. The symptomatology, risk factors, laboratory, radiological profile, and outcomes were recorded using tables and percentages. The quantitative, qualitative, and categorical variables have been analyzed using the SPSS version 23 software, and the results were expressed in percentages with appropriate tables.
| Results|| |
Out of 72 patients, 47 patients (65%) were male and 25 patients (35%) were female. 11 (15%) patients were <45 years, 24 patients (33%) belonged to the age group 45–65 years and 37 patients (51%) above 65 years [Table 1].
Forty five patients (63%) when previously admitted, belonged to severe and 19 (26%) to moderate category at presentation, the remainder, i.e., 8 (11%) belonged to the mild category [Table 2]. Retrospectively, it was found that, the severe cases were admitted in the intensive care unit (ICU) requiring noninvasive and invasive mechanical ventilation, whereas the mild and moderate cases were treated in the wards and High Dependency Unit (HDU), respectively. The moderate groups were treated with high nasal flow oxygen therapy.
All the patients were treated with standard treatment guidelines according to Ministry of Health and Family Welfare 03/06/2020 guidelines.
Progression of severity
Three patients of mild category progressed to moderate within 8 days, requiring nasal oxygen therapy. Eight patients of moderate category progressed to severe within 7 days, requiring noninvasive ventilation and invasive mechanical ventilation. Average duration of stay was 17 days.
Fifty three patients (74%) had persistent symptoms most commonly being respiratory, in the form of dyspnea on exertion, chronic dry cough, sore throat, and fever [Table 3].
Out of them, 18 patients (25%) had lesser than the lower limit of 6-min walk test.
Forty-seven patients (88.6%) showed persistent radiological abnormalities – 32 patients having ground-glass opacities, five patients having interstitial thickening, two patients having crazy-paving patterns, and eight patients having features suggestive of pulmonary fibrosis on high-resolution computed tomography (HRCT) thorax imaging.
Pulmonary function testing was done in 12 patients who had no previous comorbidities. Of these 9 showed a persistent restrictive pattern, whereas the remainder showed an obstructive pattern.
Exertional dyspnea was present in 17 patients, with Grade 2 Modified Medical Research Council (MMRC) seen in four patients, Grade 3 MMRC in six patients and Grade 4 MMRC in seven patients.
Nine patients presented with fever associated with lung signs and muscle manifestations [Table 3], out of which 6 had low grade fever and 3 had high grade fever.
Persistent musculoskeletal symptoms such as fatigue, generalized myalgia, and joint pain were seen in 40 patients (56%) [Table 4].
On examination, 16 patients had muscle tenderness, seven patients were febrile, six patients had swelling of the extremities, and 5 had elevated creatine phosphokinase levels. It was found that retrospectively in the previous admission for COVID-19 infection, majority of these patients were of severe category, requiring admission in the ICU and had a prolonged duration of stay in the hospital.
Neurological manifestations such as persistent anosmia, dysgeusia (like metallic taste and disturbance of taste), headache (located holocranial followed by frontal, dull aching in character, continuous in nature with no aggravating factors, relieved on nonsteroidal anti-inflammatory drugs), sleep disorders, and giddiness were seen in 14 patients (19%) [Table 5].
Sleep disorder manifestations were in the form of difficulty in initiating sleep, frequent awakenings and excessive daytime sleepiness, snoring, and restless sensation in the legs seen in 11 patients. One patient had a prior history of cataplexy; however, cataplexy was not observed during our study and the patient presented with sleep disturbances in the form of excessive daytime sleepiness. Majority of them were women with depressive illness followed by anxiety disorder. Sleep studies were done in two patients as they presented with significant sleep disturbances, which were inferred to be normal.
One patient presented with new onset seizure activity and one presented with sudden onset left sided hemiparesis. These patients were further diagnosed to have acute hemorrhagic and right MCA territory acute ischemic stroke on neuroimaging, respectively.
Eight (11%) patients had reduced quality of life with more problems in performing daily-life activities and active psychiatric illness with memory and sleep disturbances, behavioral, and mood abnormalities. This was in the form of varying degrees of depression, anxiety, mania, and posttraumatic stress disorder. The multi-dimensional quality of life scale score was impaired in a majority of them.
Two patients had a prior history of psychiatric illness, i.e., schizophrenia and psychosis, were on treatment.
Gastrointestinal manifestations such as anorexia, watery diarrhea, nausea, and vomiting were seen in seven patients (10%) [Table 6]. Symptoms such as anorexia and nausea were persistent manifestations postacute COVID-19, whereas vomiting and diarrhea were new onset symptoms with an average duration of 6 days. Other possible causes for these symptoms were ruled out.
Four patients came with cardiac manifestations in the form of heart failure, myocarditis, and acute coronary syndrome non-ST-elevation myocardial infarction. All patients had associated preexisting illness such as diabetes mellitus and systemic hypertension and ischemic heart disease. These patients were evaluated with electrocardiogram, 2-dimensional ECHO, and cardiac specific biomarkers.
Three patients presented with calf muscle pain and tenderness on examination. D-Dimer levels were elevated in all the patients. Two patients demonstrated features suggestive of deep venous thrombosis on lower limb venous Doppler, whereas one patient had confirmatory features of pulmonary embolism on contrast-enhanced CT thorax.
One patient presented with complaints of reduced urinary output. The patient was a known case of chronic kidney disease-stage 3. On evaluation, he was diagnosed to have acute on chronic kidney disease, with serum creatinine of 3.7 mg/dl, blood urea nitrogen levels of 82 mg/dl. The patient had prior history of fever with generalized myalgia. Creatine phosphokinase levels were found to be 1733 mcg/L.
Forty five (63%) patients had underlying preexisting illness, as shown in [Table 7].
Inflammatory markers such as serum ferritin, erythrocyte sedimentation rate, C-reactive protein, lactate dehydrogenase, and D-dimer levels were elevated in 50 (69%) patients at the time of presentation in the post-COVID state. Persistent elevation of these markers was seen in a majority of them.
Mortality was seen in four patients (5.55%), the cause being acute coronary syndrome followed by pulmonary embolism, acute hemorrhagic stroke, and acute respiratory distress syndrome (ARDS).
| Discussion|| |
In our study, majority of patients presenting with post-COVID-19 sequelae were the elderly with comorbidities and history of prior ICU admission when admitted for COVID-19 under severe category. The mean hospital stay for these patients was 5 days, the highest being for those with respiratory symptoms who had a mean hospital stay of 8 days.
Goërtz et al. in a study of post-COVID-19 in 112 hospitalized and 2001 nonhospitalized patients who were followed up for 3 months, found that risk factors for hospitalization due to post-COVID-19 included older age, male gender, concurrent comorbidities and higher body mass index, and history of hospitalization. Moreover, as opposed to the postsyndromes of other respiratory infections, a wide range of atypical symptoms such as palpitations, headache, ageusia, diarrhea, anosmia, and fever were recorded months after the infection.
Majority of the patients included in our study came with persistent symptoms in the form of respiratory manifestations such as dyspnea on exertion and nonproductive cough, which was predominant, followed by musculoskeletal and neuropsychiatric symptoms. Other presentations were cardiac, thromboembolic manifestations, and acute kidney injury.
A descriptive analysis based on ICU admissions of 103 patients across 6 medical centers in Norway by Lerum et al. found that on a 3 months' follow-up approximately 50% patients presented with persistent dyspnea on exertion and 25% of the participants had changes in chest CT and reduced diffusing capacity. Participants admitted to ICU during hospitalization presented with more CT abnormalities and reported more problems in daily-life activities in comparison to those not admitted to ICU.
In a review article based on postacute COVID-19 syndrome by Nalbandian et al., the residual effects of SARS-CoV-2 infection, such as fatigue, dyspnea, chest pain, cognitive disturbance, arthralgia, and decline in quality of life were found to be common. Cellular damage, a robust innate immune response with inflammatory cytokine production, and a pro-coagulant state induced by SARS-CoV-2 infection have been postulated to contribute to these sequelae.
An observational cohort study from 38 hospitals in Michigan, US evaluated the outcomes of 1250 patients who were discharged, in which 15.1% required readmission. 32.6% of patients reported persistent symptoms, in which dyspnea while climbing stairs was most commonly reported followed by cough, and persistence of loss of smell and taste.
A postacute outpatient service established in Italy reported persistence of symptoms in 87.4% of 143 patients discharged from the hospital, in which fatigue was the most common symptom reported followed by dyspnea, joint pain, and chest pain.
In a survey by the UK Government's Office for National Statistics in November, 2020, around one in five people who tested positive for COVID-19 had symptoms that lasted for 5 weeks or longer, and one in ten people had symptoms that lasted for 12 weeks or longer.
Huang et al. studied the 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study in which anxiety and depression was reported among 23% of patients with critical illness.
Long-term psychological distress and posttraumatic stress disorder can develop in more than half of the patients who survive.,,,
Nearly half the patients presenting with persistent respiratory symptoms and fatigue showed evidence of pulmonary fibrosis on HRCT thorax.
In persistent post-COVID syndrome, the inflammatory response is repressed too far in the direction of compensatory anti-inflammatory response syndrome, then the patient, having managed to “weather” the initial hyper inflammatory cytokine storm and the progression to ARDS, may enter a stage of protracted immunosuppression which is one of the hypothesized causes.,,
In addition to the loss of immune competence, they are also vulnerable to the development of pulmonary fibrosis.,,
TGF beta is a multifunctional cytokine with pro-fibro genic, anti-inflammatory, and immunosuppressive effects, and is found to be elevated during and after sepsis as well as during and after COVID-19, presumably to counteract the hyper inflammatory response.,,,
The fibro-proliferative phase of ARDS, activation of collagen synthesis and secretion of TGF beta secondary to mechanical ventilation in COVID-19 have been some possible causes of pulmonary fibrosis COVID-19 survivors.,,,,
The highlight of the study is that this is perhaps the first study from this region to look at this condition. The study looked for wide range of post COVID symptoms and recorded multiple clinical manifestations.
However, to study the predisposing factors to post COVID syndrome, a longitudinal study with a follow up of all patients admitted with COVID and identifying long COVID in that cohort could have shown who are at more risk of developing long COVID. As this study was a cross sectional observation at single point in time, this is a limitation.
| Conclusions|| |
In our study it was concluded that majority of patients presenting with post-COVID-19 sequelae came with persistent respiratory symptoms. Majority of them were elderly males with comorbidities with prior ICU admission. A significant number had residual changes on repeat HRCT thorax. Hence, recovery cannot be stated when someone tests negative or is discharged from hospital. All COVID-19 survivors will require multidisciplinary post-COVID-19 clinics to address both persistent symptoms and potential long-term complications. It is necessary to recognize who is more likely to experience prolonged disease following COVID-19 infection and ensure a minimal follow-up of 6 months for such patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Department of Medicine, MVJ Medical College and Research Hospital, Hoskote, Bengaluru - 562 114, Karnataka
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]