In the final stage of the case, Dr. Sundeep Mishra discusses the concepts behind the treatment and therapies to consider for patients with viral myocarditis and heart failure, further course of action, and the responses to the questions posted in the previous part.

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For part 1, click here.

For part 2, click here.

For part 3, click here.

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Concept behind treatment in viral myocarditis

Current pharmacological heart failure therapy of myocarditis-associated cardiomyopathy mainly focuses on decreasing the activity of the neuroendocrine system (guideline mediated drug therapy– GDMT) but has minimal impact on the real culprit i.e. direct viral injury and indirect virus-induced inflammatory cardiomyopathy. When the myocardium is hugely damaged, the strategy is to merely support the failing myocardium (till it recovers) and wait and watch. Any therapy against the actual cause; virus, inflammation and immune damage induced by the virus and products of myocardial destruction is only partially successful mainly because:

• By the time diagnosis is made it is already too late
• Implicating the virus cannot be identified in majority of cases

Thus, only indirect anti-viral (IFN-β) and anti-inflammatory/immune-modulating therapy (IVIG, steroids, azathioprine etc.) can be employed which really is mostly “too little, too late”. However, the corner-stone of management in a really sick patient is essentially cardio-supportive because myocardial cells once dead, rarely regenerate. The recovery of myocardial function actually depends on the remodelling of residual myocardial tissue. Depending on the severity of the case, it may be required to support the myocardial till this re-alignment happens.

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Therapies useful in myocarditis

1. Heart failure GDMT- ACE-I/ARBS/ARNI+BB±MRAs
2. Symptomatic treatment- Diuretics for congestion, anti-arrhythmics for arrhythmias, NSAIDs for myo-pericarditis syndromes, correction of anaemia, maintaining haemodynamics etc.
3. Anti-viral treatment- Since in a majority of cases, the index viral infection is unidentified, no effective anti-viral therapy exists. Interferon-beta (IFN-β) can help in some cases (with persistent adenovirus or enterovirus infection). After the initial run-in period to improve tolerance, patients receive 2 x 10⁶ IU IFN-β per application every other day for 1 week. Within the following 2 weeks, the study medication can be elevated to 4 x 10⁶ and 6 x 10⁶ IU IFN-β, respectively, and continued for the following 21 weeks.
4. Anti-inflammatory Rx- Myocardial inflammatory processes due to pathogenic autoimmunity may survive myocardial virus elimination and warrant immunosuppressive treatment in order to prevent later immune-mediated myocardial injury. Drugs that can be administered are immunoglobulins, corticosteroids, azathioprine, and cyclosporine, which are administered on top of regular heart failure medication.
5. Intravenous immunoglobulin (IgG, IgA, and IgM) have both anti-inflammatory and antiviral effects. IVIG may replace antibodies, enhance viral clearance, neutralise pathogens, and enhance clearance of inflammatory cytokines that contribute to myocyte destruction. IVIG regimen with a dosage of 2 g/kg for 1 day, and 400 mg/kg/day for 5 days.
6. α-Methylprednisolone is generally given at a dose of 1 mg/kg body weight, initially for 4 weeks. In children, IV predinisolone can also be given. The steroid dosage is titrated down every 2 weeks in increments of 10 mg until a maintenance dose of 10 mg is reached. The treatment duration should last for 3 to 6 months.
7. Azathioprine is administered depending on the weight (100 to 150 mg daily) in addition to the corticosteroid.
8. Cardiac assistance- If there is a huge amount of myocardial damage leading to cardiogenic shock, mechanical circulatory support with ventricular assist devices or extracorporeal membrane oxygenation support is beneficial as a bridge to transplantation or recovery in adults and children to tide over the time till re-modelling and recovery can happen.

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Our case

Analysis: While the case apparently seems to be on path of recovery:

• Patient became comfortable
• Stabilisation of haemodynamics (SBP >100, good urine output)
• Correction of salt and water balance (normal electrolytes, ABG- no acidosis)
• Improvement of ventilator status (SAO2- 100%, off NIV)

This apparent improvement is only an illusion (because it is only symptomatic improvement related to treatment administered). In reality, the patient has actually worsened as evidenced by;

• Worsening cardiac enzyme values (▲ Troponin T from 0.15 → 21.8 ng/mL→25 ng/mL; ▲ CK-MB from 77 ng/mL→104 ng/ml)
• Worsening BNP (8270 → 8420 ρg/ml)
• Worsening inflammatory markers (▲ TLC 10300 → 12400).

Thus, the patient has an ongoing inflammatory response and ongoing myocardial damage and is really much sicker than what she was before she came in.

The course: The very next day the patient had,

• Developed persistent orthopnea with oxygen requirement; finally, patient got intubated and received mechanical ventilation in view of worsening sensorium
• Patient also developed worsening hypotension with decreasing urine output
• There was no fever

ABG was suggestive of severe mixed acidosis and hypoxemia (pH-6.98, pCO2-68, pO2-20, HCO3-16, BE-8, Lactate-8).

Lab investigations

Hb	9	9.5	8.5
TLC	10300	12400	15600
PLT	2.1L	2.9L	1.4L
DLC	71/20
INR/aPTT	1.3		2.1
Na	130	135	131
K	3	4.9	3.9
Urea	31	34	101
Creatinine	0.6	0.8	2.2
BIL	0.6	0.6
SGOT/SGPT	151/261		654/816

CXR: No change

Echocardiography: Some RA/RV dilatation but no increase in pericardial effusion.

Analysis: Thus, there is ↑TLC, worsening renal and liver functions, worsening salt and water balance as well and evidence of further worsening of ventricular function.

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What do we do now?

Since the basic issue is worsening cardiac function (due to ongoing myocardial injury/damage), the only way to save the patient is to provide cardiac support even if temporary.

1. Cardiac assist device- Despite cost constraints, ECMO was advised (the cost borne by our institution- AIIMS). Veno-Arterial ECMO was initiated immediately. ECMO pump flows of 2.2 l/min was achieved, initially sweep gas was kept 2.0 l/min with FiO2 of 1.
2. The patient was started on dopamine and nor-adrenalin as well.
3. In view of ongoing inflammatory insult she was started on Azathioprine is 100 mg daily in addition to corticosteroids.
4. Salt and water balance was managed as before based on PCWP and electrolyte values.
5. She was also started on higher antibiotics (Piperacillin & Tazobactam) empirically.
6. She was put on mechanical ventilation with PEEP as already discussed.

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Further course

Soon after ECMO initiation inotropes could be weaned to minimal support with dobutamine. Ventilation was weaned to moderate settings (PEEP 8, rate 18/min and FiO2 50%). There was gradual improvement in cardiac function and was decannulated from ECMO on 12th day after weaning trials (patient requiring minimal ionotropes).

Another 2 days later, the patient was weaned off from mechanical ventilation also. Subsequently during hospital stay, cardiac function was monitored regularly with serial clinical examinations and 2D echo which were suggestive of near normalisation of cardiac function. She was discharged to home after 28 days of admission with complete clinical recovery. Patient did not require cardiac transplantation but was instructed not to undertake heavy exertion for at least 6 months and only after follow-up echocardiography.

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Answers to questions

Question1: Are we on the right track?

To this all the respondents who replied in affirmative (that we are on the right track) but as can be seen that like us all, are mistaken by the symptomatic improvement observed as evidenced by patient becoming comfortable, stabilisation of haemodynamics (SBP >100, good urine output), correction of salt and water balance (normal electrolytes, ABG- no acidosis) and improvement of ventilator status (SAO2- 100%, off NIV). However, this is only a momentary respite due to appropriate use of medications.

On the other hand, the patient has actually worsened (more myocardial damage) as evidenced by worsening cardiac enzyme values, worsening BNP and worsening of inflammatory markers. All these parameters really suggested that the patient required a cardiac assist device like ECMO to tide over acute crisis and the window of opportunity is actually before the final worsening happens. Institution of EMO after the worsening has already happened leads to only 50 to 60% survival. We were lucky that our patient survived even though we initiated ECMO a bit late.

Question 2: Are any further investigations necessary? EMB?

Again, while most respondents suggested repeating of cardiac biomarkers, inflammatory markers even repeat MRI but none of them advised cardiac endomyocardial biopsy.

EMB not required?

While EMB was considered a gold standard for diagnosis of myocarditis in the past, currently it has been overtaken by cardiac MRI. The reason for this fall in grace is attributed to its low sensitivity (variability in interpretation, sampling error etc.), low availability, and risk of an invasive procedure. Currently, this procedure is only used in diagnosis of cardiac transplant rejection or in 2 other clinical scenarios; unexplained new-onset heart failure of <2 weeks duration associated with a normal-sized or dilated left ventricle in addition to haemodynamic compromise or unexplained new-onset HF of 2 weeks to 3 months duration associated with a dilated left ventricle and new arrhythmias such as ventricular arrhythmias, Mobitz type II 20 AV block, 30 AV block, or failure to respond to usual care within 1 to 2 weeks. None of these scenarios were prevalent with our case, so EMB was not required here.

Question 3: Is any further treatment necessary?

Most respondents felt that what we were doing was enough. A few suggested IV iron or change in antibiotics while none suggested a need for a cardiac assist device at this stage. A retrospective pondering in our case suggests that use of ECMO was perhaps life-saving for her while other maneuvers including immune-modulating therapy and other therapeutic changes were supportive in nature.

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Take home messages

1. Clinical diagnosis of myocarditis may not be straight-forward (mixed clinical manifestations- it can mimic myocardial infarction, idiopathic DCM, arrhythmogenic disease etc.) and requires a healthy “suspicion” on the part of the treating physician.
2. Endomyocardial biopsy is no longer the gold standard because of poor sensitivity, low availability and it being of invasive nature (requiring cardiac catheterisation).
3. Viral serological tests are also not useful because of poor sensitivity and a lack of evidence regarding their clinical utility.
4. Currently, cardiac MRI is the gold-standard for diagnosis because it offers a non-invasive, reliable tool with additional advantages of repeatability, non-invasiveness and ability to prognosticate the disease. The diagnosis can be made on the basis of epicardial and mid-wall inflammation and edema and sub-epicardial scarring.
5. The course of the disease can be monitored by the rising/falling levels of cardiac enzymes (Troponin, CK-MB), BNP, inflammatory markers (CRP, TLC, ESR etc), echocardiography and even cardiac MRI.
6. Treatment of myocarditis is mainly supportive (GDMT for heart failure) and symptomatic (mantaince of haemodynamics, salt and water balance, acid-base balance, ventilation) with a little role of anti-viral therapy (direct or indirect like IFN-β) or anti-inflammatory (IVIG, steroids or azathioprine).
7. Sick patients with haemodynamic compromise require a timely institution of a cardiac assist device like ECMO, short of that prognosis can be very poor.
8. With institution of proper therapy most patients will recover and many may not require cardiac transplantation.

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Final note

I have brought a real case to you with a real-world management with usual hits and misses as are there would be with any case. I would be grateful if you send me your clinical insights as well as your comments and suggestions as to how to make it more attractive and informative.

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This is a special, real-life case challenge series. Stay tuned for another interesting case and the expert's discussion of the answers to the questions posted.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author, Dr. Sundeep Mishra is a Professor of Cardiology.