Review

COVID-19 is prevalent across all age group, but frequently it is observed as a disease of elderly patients with more severity.As per initial observation, overall hospitalization rate due to COVID-19 was around 5/100,000 population; but in the elderlypopulation, it was three times higher; which is around 15/100,000 population.⁵ 70% of these patients are either asymptomaticor have mild symptoms including mild fever, cough (dry), sore throat, nasal congestion, malaise, headache, muscle pain.

Only in 30%, there will be continuous fever with respiratory complications; that may require intensive care unit (ICU)admissions.⁶ Routinely COVID-19 treatment is given in home with the objective of further prevention of disease. Usually, itcan be managed through counselling, controlling fever, proper hydration. Detailed guidelines for critical care managementfor COVID-19 have been published by the WHO.⁷

Interestingly, specific comorbidities including hypertension, diabetes mellitus, obesity, chronic lung disease, renaldiseases, myocardial infarction, immunosuppressive disorders, gastrointestinal disorders are frequently associated withCOVID-19, which are responsible for increased risk of infection and worse outcomes with increased severity of lung injuryand mortality have been reported. After 3 months of this pandemic outbreak, some initial reports from majorly affected citieslike Wuhan, Lombardy, and New York City identified higher rates of hypertension, obesity and diabetes among severely ill,hospitalized COVID-19 patients.⁸ As per Garg S et al., the top 3 comorbid conditions including hypertension (~50%) andmetabolic conditions like obesity (~48%) and diabetes (28%) were associated with hospitalization due to COVID-19.⁵

Since it is a global pandemic and more than 90% of the affected persons will finally recover from the acute phase, wecan expect a large number of the population who would be recovering from the acute illness soon and would be having manyshort-term and long-term morbidities. Long-term outcomes and squeal of COVID-19 are difficult to predict at present, butwe can extrapolate the knowledge acquired from previous respiratory outbreaks produced by coronaviruses like the SARS(severe acute respiratory syndrome) CoV of 2003 and the MERS CoV of 2012.⁹

Currently, it is very difficult to predict long term outcome of COVID-19 in various systems of the body, but we can assessthe short term and long-term respiratory sequelae of COVID-19 to be on similar to that of individuals affected with previouscoronavirus pandemics like the SARS and MERS. There are studies to suggest a significant residual damage in the pulmonaryparenchyma with impairment in surface area of gas exchange in 15.5% and 24% of survivors of SARS after 6 months and2 years after recovery respectively.^10,11 Zhang et al. in their observational follow-up study of SARS survivors, showed thatthough the imaging abnormalities on computerized tomography (CT) scan had improved significantly after 2 years of theacute illness, but subtle diffusion abnormalities persisted after 15 years of follow-up.¹² Apart from this, SARS and MERSinduced mental stress, psychological distress and reduced quality of life have been observed not only 1 year and 4 years postillness but the emotional and mental health remained lower than controls even 12 years later.^13,14 These findings signify theimportance of evaluation of long-term effect of COVID-19 on endocrine system-related diseases in survivors

In the last 8 months, COVID-19 and its association with the elder age group, hypertension, diabetes, obesity, chroniclung disease, etc. are frequently observed. The affection of COVID-19 with renin angiotensin system (RAAS) axis, beta celldysfunction and insulin resistance leading to diabetes, abnormalities in lipid profile and long-term derangements of variousmetabolomes, glucocorticoid axis and thyroid gland abnormalities are important causes of our concern

SARS-CoV and SARS-CoV-2 utilize angiotensin-converting enzyme 2 (ACE2) as receptors for internalization into the hostcell. SARS-CoV-2 down-regulates the ACE2 pathway and up-regulates the more inflammatory ACE 1 pathway.¹⁵ Apartfrom respiratory alveolar epithelial cells, ACE2 is expressed in several other locations like heart, endothelium, renal tubularepithelium, intestinal epithelium, and pancreas. The long-term consequences of RAAS axis being affected by COVID-19, itssubsequent recovery and role of ACE inhibitors and DPP4 inhibitors are yet to be ascertained in long run.¹⁶

COVID-19 infection caused a lowering of serum low-density lipoprotein (LDL) cholesterol in majority and it decreasedprogressively from mild to moderate to severe disease. Serum LDL cholesterol has been proposed to be a biomarker forseverity of illness. Atherogenic dyslipidaemia was noted in 68% of the SARS survivors as compared to 40% of the healthycontrols. A study on lipid metabolism and other metabolomes in recovered SARS patients 12 years after the acute illness havenoticed raised triglyceride and very-low density lipoproteins (VLDL) levels apart from a significant rise in the levels of serummetabolomes, namely phosphatidylinositol and lysophosphatidylinositol (LPI). There are many cancer markers which have been significantly increased in patients suffering from COVID-19. A severe rise in these cancer biomarkers raise an alarm ofpotential malignancy in COVID-19 patients especially in long term survivors.^17,18

Diabetes and COVID-19 share a bidirectional link. Though the morbidities and complications of COVID-19 infection havebeen increased significantly with pre-existing diabetes, the emergence of new-onset diabetes in these patients have been aspotlight of research. Whether the hyperglycaemia during the acute illness is transient or permanent is yet to be ascertained. Toaddress these findings, an international group has formed a global registry in the name of CoviDIAB Project of patients withCOVID-19–related diabetes. The goal of the registry is to study the new-onset diabetes that is defined by hyperglycaemia,confirmed Covid-19 infection, no prior history of diabetes, and a history of a normal glycosylated haemoglobin level.¹⁹

In some of the case reports, COVID-19 was responsible for precipitating acute complication of diabetic ketoacidosis(DKA). Reddy PK et al. observed that some patients who were hospitalized with either new-onset of diabetes or with someother comorbid conditions; were also diagnosed with precipitation of DKA.²⁰ In those two cases, interleukin 6 (IL-6) levelsis elevated in both DKA and COVID-19, which may be an important prognostic factor. The possible mechanism may beaggressive damage to beta cells of the pancreas or abnormal secretion of insulin due to downregulation of ACE2 cells inthe pancrease.²⁰ In the current scenario, there is no major change is recommended for the management of diabetes withCOVID-19, but strict glycaemic control is at most important, which can be achieved by extensive anti-diabetic medications.But for long-term control, metformin has shown its beneficial effect by reducing mortality in these types of patients.²¹ Otheranti-diabetic drugs are also recommended, but need to address clinical outcomes and predictors in the case of SARS-CoV-2exposure with long-term effect.²²

Irrespective of the use of glucocorticoids during acute SAARS event, endocrine evaluation of survivors at one year haverevealed the presence of hypocortisolism in around 39% individuals.²³ Reversible hypophysitis or direct hypothalamic effectleading to the hypothalamic-pituitary-adrenal (HPA) axis suppression have been proposed to be the responsible mechanism.HPA axis dysfunction of the majority resolved within a year but one should be careful about its long-term implications. Thehypocortisolism probably explains the persistence of weakness, fatigue and poor quality of life long after recovery from theacute infection. Evaluation of the HPA axis in follow-up visits should be done to rule out central adrenal insufficiency, inCOVID-19 patients as well.

In one observational study of SARS, 7% hypothyroidism was reported in survivors, with histopathological changes includingaltered follicular architecture with distortion, dilatation, and collapse.^24,25 Initial stage of subacute thyroiditis with a raisedlevel of inflammatory markers may also lead to hypothyroidism on long-term follow-up. At the moment there are no datasuggesting that thyroid patients are at higher risk of COVID-19, but this requires further research and data analysis.²⁶

Since we are expecting a mammoth number of people recovering after the COVID-19 infection, our state, nation and theentire world need to foresee, what short term and long-term complications these COVID-19 survivors may have in future andaccordingly robust planning and strategy need to be kept in place. The goal is to improve discharged COVID-19 patients’breathing difficulties and dysfunctions, reduce complications, relieve anxiety and depression, reduce disability rate, restorethe capacity for routine activities as much as possible and improve quality of life. Apart from respiratory function and physicalrehabilitation a strong psychological and emotional support and rehabilitation is a must for all COVID-19 survivors. ^27,28

Endovigilance is the key to prevent any diabetes and endocrine-related complications in the long run. Both the patientand the physician should be absolutely vigilant for any new onset dysglyceamia and diabetes and if detected, need to betreated. Thyroid function evaluation can be done at the recovery phase and long run as there are evidences of thyroiditisand hypothyroidism in the previous respiratory pandemics. Evaluation of the HPA axis is to be done in any COVID-19survivor, presenting with extreme fatigue, anaemia, low blood pressure and altered electrolytes. Since there are evidencesfor dyslipidaemia in both acute infection and in long-term, COVID-19 survivors are to be actively screened for any lipidabnormalities and atherosclerotic cardiovascular diseases.²⁹

Though COVID-19 is an acute viral infection predominantly affecting the respiratory system, it has long term metabolic andendocrine implications. Being a global pandemic with a high rate of recovery, it is expected to find many long-term metaboliccomplications in a vast number of COVID-19 survivors. Hence, it is prudent to be vigilant to detect these metabolic andendocrine complications and plan out a robust rehabilitation and management plan at the earliest.

The author declares absence of any conflict of interest.

No funds were received for publishing this article.