To the doctors in our Group. I received this today with details of Covid 19 management from Prof MS Seshadri , co authored by Prof T Jacob John, Former Head of Clinical Virology, Christian Medical College, Vellore.

Read on. Thank you. Dr John Thanakumar.

COVID 19 pandemic : defining the clinical syndrome and describing an empirical therapy

The COVID pandemic sweeping across the world is continuing to take a heavy toll in terms of human lives, and is threatening global economy. It is currently raging unabated across several continents and the peak is yet to come. The variable sensitivity of the Polymerase chain reaction (PCR) based tests employed, different criteria for testing in different countries, limited availability of the testing facilities and the high cost of testing will exclude a large proportion of patients with the disease from the category of ‘infected cases’. Therefore alternative approaches without testing everyone with fever and cough with PCR have become necessary.

In clinical medicine, a syndrome may be diagnosed using specific clinical and simple laboratory criteria, especially when the situation is a medical emergency and treatment initiated. To cite a common example, in ‘sepsis syndrome’ , presumptive use of antibiotics, pending culture reports and completion of a course of antibiotics if there is a clinical response (even if the cultures eventually turn out to be negative) is standard practice.

In the face of a pandemic, the presence of a typical epidemiologic setting is a very important element for defining the clinical syndrome. When a disease has very high strike rate as in a pandemic, a clinical diagnosis may actually pick up more true cases than a lab test ! Further, in the present context, relying on laboratory tests only in select patients will grossly underestimate the true disease prevalence and incidence.

In view of this reality, it is important to assume that every individual with the clinical syndrome, diagnosed by criteria, has COVID 19 and to act on this surmise. This approach will be in the best interests of the individual patient, reduce health care costs and it will give a better estimate of disease prevalence and incidence..

In the light of these arguments, we recommend that the clinical syndrome be defined using criteria as listed below

Mandatory criterion:

Fever of 3 or more days duration without other obvious localizing symptoms (such as dysuria, skin or soft tissue infections)

Epidemiologic setting

1. Travel within the past 4 weeks to or from any other country or a big crowded city in the country

2. Visit within the last 4 weeks to a crowded place (bus stand , railway station, movie theatre, airport, place of worship etc)

Major criteria:

1. Dry cough

2. Sudden recent onset Anosmia or loss of taste sensation

(anosmia due to nasal block and sinusitis to be excluded)

3. Physical findings of crepitations on chest auscultation

4. Chest X Ray showing peripheral patchy infiltrate (not lobar

pneumonia or cavitating lesion)

Minor criteria

1. Diarrhoea

2. Severe headache, body aches (Myalgia)

3. Normal or low normal total WBC count and lymphopenia

( Lymphocytes < 20 % on differential count)

The clinical syndrome can be presumed to be present if

In the presence of the mandatory criterion,

1. Presence of 1 epidemiologic setting along with 2 major criteria or 1 major criterion and 1 minor criterion

2. Even in the absence of the epidemiologic setting, the presence of 2 major criteria and 2 minor criteria or one major criterion and 3 minor criteria

The availability of laboratory testing is grossly inadequate in many clinical settings. Where available, a positive lab test offers confirmation of diagnosis (in combination with clinical syndrome criteria), while a negative test does not negate the clinical diagnosis. The reason is less than optimal test sensitivity.

Therefore we can consider 2 groups of subjects

a) those having the COVID 19 clinical syndrome (large numbers)

b) confirmed cases (smaller numbers)

For those with the clinical syndrome, nasopharyngeal swabs, or even throat swabs can be sent to a regional laboratory for confirmation, if feasible, but pending results, clinical management initiated as set out below

1. Isolate affected subjects at home for a period of 2-3 weeks. Get a younger member of the family aged less than 40 to be the primary care-giver. A detailed isolation procedure at home has to be spelt out and strictly followed so as to prevent within family spread. Other family members are assumed to have been infected, hence remain in home quarantine for the next 4 weeks so as to prevent community spread. With the crowded living conditions in most middle and low income households, these measures will prove to be major challenges; isolation may not be possible in poor households living in one or two rooms. The local administration needs to face this reality and design isolation facility near home, such as a school building, if possible. The Government and non-governmental organisations (NGOs) should ensure essential supplies to these quarantined families so that they can effectively practise what is recommended.

2. As fever and cough are very common symptoms, it is essential that every household has simple medications such as paracetamol for fever and an antihistamine which will minimize sneezing and limit nasal discharge. These supplies are better issued to individual households with instructions for use, so that crowding at hospitals and medical shops is avoided. The mobile phone number of an individual in the family can be made available to the proximate primary or secondary level hospital. A designated mobile number at the health care facility can be provided to the family. Follow-up of all family members can be through a daily phone call. The follow up information can be recorded on spread-sheets

3. Chloroquine and Hydroxychloroquine (HCQ) , antimalarial drugs , have shown some efficacy in in-vitro experiments. Limited trials on infected subjects in France and China, HCQ has been shown to reduce virus load and also hasten virus clearance, from 2 weeks to 6 days. The major reasons for considering this group of drugs for presumptive treatment of the clinical syndrome are

a. Like aspirin, they have been around as essential drugs across the world for several decades. They are safe for short term use and side effects are few and well-known

b. If virus clearance occurs early, the spread from the infected individual to the others in the community will be reduced and this may help in dampening the epidemic.

c. They are inexpensive and can be made available by the Government and NGOs.

d. They have been widely used across continents for the presumptive treatment of malaria while awaiting lab confirmation; currently they are in use for Covid-19 in several places.

e. We are really clutching at straws now

In a welcome move, the Indian Council of Medical Research (ICMR) has advised HCQ chemoprophylaxis for high risk categories such as frontline health care professionals and household contacts of confirmed cases. However, since nearly 80 % of infected subjects are unlikely to be tested due to the constraints mentioned above, we need to seriously consider restricting treatment for those with the clinical syndrome and chemoprophylaxis for their contacts.

Several decades ago , presumptive diagnosis and treatment were put in place in National Malaria Eradication Programs in several countries. In a similar fashion, we suggest presumptive diagnosis of the COVID-19 syndrome and initiation of management protocol detailed below. Contacts of the subjects with the clinical syndrome can be given chemoprophylaxis with HCQ as per the advisory of the ICMR.

Due precautions are mandatory for the elderly, those with diabetes and cardiac disease. In them, dose has to be modified so to avert potential side effects of the drug

An outline of treatment, chemo prophylaxis, monitoring and precautions is detailed below.

1. Presumptive treatment: (Effective dose for treatment derived from computer assisted modelling)

Hydroxychloroquine 200 mg 2 tablets Q12h on day 1 followed by

200 mg 1 tablet Q12h for 4 more days

a. Youngsters without any risk factors : Monitor progress of clinical illness daily ( over mobile phone) Maintain a database on a spread-sheet, and avoid HCQ.

b. Avoid HCQ in those with chronic renal or liver disease

c. In subjects with diabetes mellitus:

While on HCQ, treatment, reduce dose of anti-diabetic drugs

by 25 -30 % in order to avert hypoglycaemia.

Institute home monitoring or field monitoring of blood sugars

by glucometer during HCQ treatment. Further dose

adjustment of anti-diabetic drugs can based on plasma glucose


Once the treatment course is over, over the next 3-7 days

get back to the previous stable dose of oral anti-diabetic drugs

and or insulin

d. Those with cardiac disease on medication :

Look at the drug list, look for potential drug interactions and make a considered decision in consultation with the attending cardiologist. Baseline ECG (focus on corrected QT interval) and ECG on alternate days till course is over would be useful; however, this may necessitate hospital admission. Monitor serum electrolytes and magnesium and correct hypokalemia and hypomagnesemia when detected.

Definition of contact:

House-hold contacts of the subject with presumptive diagnosis of COVID 19 syndrome (During the lock down period the members of the household are likely to be most numerous). Those working or interacting closely with the index case in the workplace (such as grocery store, post office, bank etc ) and those in migrant groups amongst whom one individual has been presumptively diagnosed to have COVID 19 clinical syndrome will also be contacts

2. Preventive treatment Regime for household and other contacts (as per ICMR advisory)

HCQ 200 mg 2 tabs twice daily for day 1 followed by

200 mg 2 tabs once a week for the next 3 weeks

Preventive treatment for contacts should be initiated as soon as the presumptive case is diagnosed. If not, it can be started any time up to day 14 of presumptive diagnosis in a member of a house-hold or group.

Long term side effects like retinopathy are dose and duration dependent and are unlikely during these short term treatment protocols

Antibiotic : In order to treat secondary bacterial infection which occurs in about 50 % of COVID- 19 cases, Azithromycin (a common antibiotic used for treating community acquired pneumonia ) 500 mg once daily for 5 days , may be added at the discretion of the treating physician based on persistent fever > 38 degree Celsius and productive cough persisting beyond 5 days

This strategy, for it to be effective, would require a quick nation-wide implementation during the shelter or lock-down period . Treatment of the clinical syndrome and chemoprophylaxis for contacts of the presumed COVIDp19 syndrome ( rather than only confirmed cases and their contacts) would be an important public health measure for all countries with resource constraints.

The Governments and NGOs involved in handling this massive human problem should seriously consider implementing this approach. They should mobilize resources, medication and manpower to do this quickly through their network of health care professionals.

The World Health Organisation has already launched a massive multinational and multi-centric clinical trial ‘Solidarity’, but the results will probably come out only after the pandemic is over! It would be good to have the outcome of the controlled clinical trials before using any interventional strategy. However in an emergency situation such as the current pandemic, where many are dying every day, it may be wise to use the drug for the clinical syndrome rather than wait and see the tragedy unfold !

Protocols by the Kerala and Maharashtra State Governments and the guidelines from the All India Institute of Medical Sciences adequately cover management of confirmed cases. We highlight the need to address the clinical COVID-19 syndrome as well

We are communicating our concerns and express our ideas as concerned medical professionals and academics with several decades of standing in the profession

Yours sincerely,

Professor M.S.Seshadri MD, PhD, FRCP(Edinburgh)

Former Professor of Medicine

CMC Hospital , Vellore

Consultant Physician, Endocrinologist & Honorary Medical Director

Thirumalai Mission Hospital,Thirumalainagar

Vanapadi Road

Ranipet 632404

Tel 04172 244520, 244521

Professor T. Jacob John FRCP (Pediatrics) , PhD (Virology),

Former Professor & Head of Clinical Virology

CMC Hospital, Vellore 02-04-2020

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