CME INDIA Presentation by Dr Basab Ghosh, Senior Diabetologist, Tripura, India.
Use steroid judiciously – Prevent Tsunami of Mucor Mycosis in India.
Steroid is anti-inflammatory drug and in COVID-19 best action is in the inflammatory stage in symptomatic cases. In Covid pneumonia the common symptoms are persistent fever, malaise, dry cough, sore throat, etc. with or without breathing difficulty.
In COVID-19, virus replicates in the viral phase i.e., first 9 days of symptoms. During this phase, steroid interferes in the replication by acceleration. So better, steroid should be avoided in the first 9 days of the symptoms.
After 9th day virus is non-replicable and non-culturable. But viral debris are present and they can be detectable up to 90 days, so RT-PCR might show positive for longer period as it detects the virus or its remnants too. These loads of viral debris are causing inflammatory response to the body-and ultimately leading to cytokine storm. So best time for anti-inflammatory steroid is in the inflammatory stage.
Indication for steroid treatment:
1) Oxygen saturation:
- SpO2 <94% indicates moderate symptomatic state and this hypoxia is the definitive guidance for initiation of steroid in moderate symptomatic cases. According to the history of clinical course of the disease, it appears in most of the cases in the second week and viral replication is getting slower in that late viral stage, so initiation of steroid is very safe.
- Six Minute Walking Test (SMWT) is a sensible test to identify future emergencies related to Covid pneumonia and action should be taken accordingly as per situation. In high-risk group if SMWT is positive, steroid should be initiated safely if clinically it is in second week. SMWT should be an important clinical tool for the COVID-19 management.
2) Clinical Pneumonia:
Clinically in moderate symptomatic cases steroid should be initiated in second week:
- If temperature is persistently high >100-degree F in spite of Paracetamol treatment for more than 4 to 5 days.
- If pulse rate (PR) is high >110/min in a state of fever, where temperature measurement is not possible, for more than 4 to 5 days.
- If respiratory rate (RR) is >24/min for a reasonable period. Clinically RR is a reliable parameter to assess severity of Covid pneumonia. RR is 21 to 24 in mild symptomatic cases, in moderate symptomatic cases 25 to 30 and in severe cases >30 per minute.
3) CT scan chest:
- If CT scan chest shows CORAD 12/25 scoring, it indicates 50% lung involvement due to Covid pneumonia. In such cases steroid must be initiated according to risk assessment management, may be keeping viral stage in consideration.
- Without current scientific evidence behind the below complete statement, for the easy approach to the clinical management of COVID-19 on the basis of gathered clinical and radiological features of COVID-19, I would like to assume:
- Oxygen saturation <94% = Moderate disease = CORAD score 12 /25 = 50% lung is involved.
Choice of steroid:
- The clinically significant RECOVERY Trial is conducted with Dexamethasone, might be that brings more inclination to this molecule in the management of COVID-19. However, among the steroids, Methylprednisolone is better than Dexamethasone and Dexamethasone is better than Prednisolone.
- Methylprednisolone penetrates much better into the lungs and also binds better with the glucocorticoid receptors among all steroids, so it gives better anti-inflammatory response. We must remember for steroid treatment right time, right drug, right dose and right treatment duration are vital in patients’ outcomes.
- Evidential Covid pneumonia is established in the moderate symptomatic cases by radiological tests; CT scan confirms earliest on 2 to 3 days and x-ray chest confirms on 5 to 7 days of symptoms.
- Though many experts differ in their views, the dictum for steroid treatment in COVID-19 should be “start early when the patient develops pulmonary sign either clinically or radiologically”.
- Without moderate symptomatic cases, initiation of steroid in the first week in mild symptomatic cases is controversial and it should not be done as it’s in the early viral replication phase and that may worsen the case to critical later in cytokine storm.
CME INDIA Learning Points
Deciding points for steroid treatment initiation.
A) Monitoring of four parameters by the patient or attenders at home quarantine and in Covid Care Centre (CCC) can save emergency:
2) Temperature with clinical thermometer, clinically with counting pulse rate
4) Respiratory rate counting
B) Six-Minute Walk Test (SMWT)
C) Steroid doses
D) The landmark RECOVERY trial published in June 2020 has served as a ‘license’ to use steroids in patients with COVID-19. However, the fine print clearly revealed some important messages that we seem to have overlooked. Benefit was specifically shown with low dose, short duration dexamethasone in moderate to severe illness. Although, higher doses and longer durations may be used in exceptional cases due to compelling reasons, such patients should be evaluated for undiagnosed diabetes, checked for strict glycaemic control and closely monitored for secondary infections. A cavalier attitude to the use of steroids should be discouraged.
E) High blood sugar and low immune function are the strongest risk factors for Mucor mycosis. Patients most vulnerable to mucormycotic are those who have been treated with steroids and other drugs for COVID-19, to reduce inflammation.
F) The use of corticosteroid treatment and anti-IL-6-directed strategies in the highly susceptible COVID-19 hosts along with high fungal spore counts in the environment creates the perfect setting for mould infections.
G) Post COVID-19 sepsis including Mucor mycosis is what occurs after SARS- CoV-2 has had a rampage in the human body and we are literally left picking up the pieces. It leads to a dysregulated innate immune response, ciliary dysfunction, cytokine storm, thrombo-inflammation, microvascular coagulation and eventual immune exhaustion. This cascade of events facilitates secondary bacterial and fungal infections especially in critically ill patients subjected to emergency invasive procedures, mechanical ventilation, CRRT, ECMO, poor nursing ratios, prolonged hospital stays and breaches in asepsis. In such background, irrational use of steroid creates the perfect setting for mould infections, leading to Mucor mycosis.
H) The most commonly affected areas by mucor include nose, sinuses, eyes and brain. Patients discharged after COVID-19 should be taught to seek immediate medical attention, should they notice any symptoms such as: facial swelling, pain, numbness, eye swelling, bloody or black- brown discharge from the nose. In addition, since most doctors have only a passing knowledge about mucor mycosis, they need to be made aware about how to suspect it and proceed with the diagnostic and therapeutic strategies.
Prevent Tsunami of Mucor Mycosis
Dr Shashank Joshi, Endocrinologist, Mumbai shares:
- With rampant use steroids India will have high Mucor mycosis. Every patient is different in treatment with steroids and should use best judgement when to treat with steroids. Maximum dose in Covid is 40 mg bid. You cannot t go above 120 mg. We are having a tsunami of mucor myocos.
- For mucor mycosis, Michigan trial used dose of 40 mg bid. That’s the evidence.
Dr Pritam Chatterjee, DM, Card, Kolkata shares:
- We have seen many patients who recover from Covid infection after oxygen and or ventilator therapy from ICU gets Mucor mycosis… And after that it’s related complications. It’s our observation that the humidifier bottle attached to oxygen tube is filled with water and in most centres, they use non-sterile tap water which contains lots of microorganisms. Oxygen passes from that water is rich of microorganisms and patients are immunocompromised due to various illness and systemic steroids. So, all these favours to infect the patients especially mucor mycosis. So, it is advisable to fill the bottle with only and only sterile water and change water regularly and from pt to pt, we can reduce mucor mycosis.
Dr Santosh Malpani, Nanded:
- I have come across 3 cases who had been given very short course of steroids, non-diabetic, having mucor now. There must be some association of mucor and this strain of COVID. Please counsel all patients about unilateral headache, which is a common symptom.
High dose Steroids vs Low dose
- Systemic corticosteroids have always been controversial in treating viral pneumonia. A newly published meta-analysis demonstrated that corticosteroid treatment was associated with longer length of stay, higher probability of bacterial infection, and mortality among patients with coronavirus pneumonia (1)
- High-dose but not low-dose corticosteroids were found to potentially increase the mortality of patients with severe COVID-19 (2). Therefore, high-dose corticosteroids should be used with extreme caution in treating COVID-19.
- Low‐dose systemic corticosteroids are strongly recommended by the WHO for COVID‐19 patients with hypoxia. Yet, the optimal dose is still not clear. Higher doses of corticosteroids may offer additional anti‐inflammatory effects, but maybe also a be associated with a higher risk of serious adverse events.
- The COVID STEROID 2 trial intends to provide important evidence on the optimal dosing of corticosteroids for COVID‐19 patients with severe hypoxia. (Ongoing Trial).
High-dose corticosteroid pulse therapy (HDCPT)
- High dose corticosteroid pulse therapy is usually defined as a daily dose of at least 1.5mg/kg/24h of methylprednisolone or dexamethasone equivalent.
- High dose corticosteroid pulses were given to patients in one trial as per following criteria.
IL-6 of at least 40 pg/ml and/or two of these: ferritin, triglycerides and D-dimer of at least 300 ng/ml, 300 mg/L and 1000 ng/ml respectively.
- HDCPT was administered right after the detection of these marker levels independently of whether the patient was in intensive care or not.
- Low dose corticosteroid therapy is usually defined as lower than 1.5mg/kg/24h of methylprednisolone or dexamethasone equivalent.
- One recent study concludes: It can be an effective intervention to increase COVID-19 survival rates in patients at risk of developing a COVID-19 hyper-inflammatory response, laboratory marker tests can be used to stratify these patients who should be given HDCPT. This study was not a randomized clinical trial (RCT). (3)
- Yang Z, Liu J, Zhou Y, et al. The effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta-analysis. J Infect 2020; 81:e13–20.
- Sijia Li, Zhigang Hu, Xinyu Song, High-dose but Not Low-dose Corticosteroids Potentially Delay Viral Shedding of Patients With COVID-19, Clinical Infectious Diseases, Volume 72, Issue 7, 1 April 2021, Pages 1297–1298, https://doi.org/10.1093/cid/ciaa829.
- López Zúñiga MÁ, Moreno-Moral A, Ocaña-Granados A, Padilla-Moreno FA, Castillo-Fernández AM, Guillamón-Fernández D, et al. (2021) High-dose corticosteroid pulse therapy increases the survival rate in COVID-19 patients at risk of hyper-inflammatory response. PLoS ONE 16(1): e0243964. https://doi.org/10.1371/journal.pone.0243964.
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