COVID and Hydroxychloroquine

Cite this article as:
Alison Boast. COVID and Hydroxychloroquine, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.24968

There has been lots of media attention around hydroxychloroquine use for COVID-19 in recent days, largely stemming from this press release where Donald Trump discussed its effectiveness.

 

However, as many have since pointed out, the evidence is very limited, and care needs to be taken when trying new drugs in a clinical context, even in a pandemic. There are many risks associated with using a drug for a new indication, particularly in patients who are otherwise unwell.

 

What is hydroxychloroquine?

Hydroxychloroquine is a prescription medication currently used in both adults and children for autoimmune diseases including lupus and for the treatment of malaria.

 

What is the evidence so far?

The evidence for hydroxychloroquine can be divided into two types – in vitro (in the test tube) and in vivo (in people).

In vitro evidence

The in vitro evidence for hydroxychloroquine is promising. It works in two ways:

  1. Direct inhibition of SARS-CoV-2
  2. Immune modulation

Severe disease occurs in COVID-19 due to the pro-inflammatory cascade and cytokine sstorm causing acute respiratory distress syndrome (ARDS). The inflammatory cytokine interleukin-6 (IL-6) has been particularly implicated in this pathway, and there is evidence to show that hydroxychloroquine has anti-inflammatory effects decreasing the production of a number of cytokines including IL-6.

In vivo evidence

The evidence for hydroxychloroquine in COVID-19 is currently limited to a few small prospective studies in adults. These studies have many methodological limitations increasing the risk of bias, and more randomised controlled trials are required before commenting on its efficacy. There are also concerning reports of cardiac toxicity with hydroxychloroquine use, which highlights the importance of only using new drugs in the context of clinical trials.

 

What evidence is there in children?

In short – none!

So far there have been no clinical trials of hydroxychloroquine in children. As it is already used in children with other conditions, we do know that is safe in the ‘well’ child and have some information about appropriate dosing. However, if it is prescribed to children with moderate to severe disease COVID-19, we cannot assume that the distribution around the body and clearance (pharmacokinetics) and its interaction with the body (pharmacodynamics) is the same.

 

Where to from here?

As per the World Health Organisation experimental therapies should not be used outside of registered clinical trials. The future use of hydroxychloroquine in children with COVID-19 is therefore dependent on whether clinical trials are conducted.

 

Why is this important?

For any new therapeutic agent to be used in children it requires the same rigorous assessment in clinical trials in adults. Often due to ethical issues and the inherent challenges of performing clinical trials with children, these studies do not occur. This is a huge issue in paediatrics in general, as almost all new drugs are only tested thoroughly in adults.

Paediatricians are often forced to prescribe drugs ‘off label’ (use of drugs for a different age group, indication, dosage, frequency or route) or ‘unlicensed’ (where a drug is used despite it not being approved by the licencing body such as Therapeutic Goods Australia). Many commonly used drugs are actually prescribed ‘off label’ including ondansetron, salbutamol and even paracetamol. There are well-documented risks of adverse effects with off-label and unlicensed prescribing. Without clinical trials there is no other option.

 

In conclusion…

It would be great if hydroxychloroquine was the wonder-drug we were all waiting for, with the in vitro data certainly promising. However, further clinical trials to assess its efficacy and safety are required, particularly before its use in children.

 

References

Liu J, Cao R, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6:16.

Mackenzie AH. Dose refinements in long-term therapy of rheumatoid arthritis with antimalarials. Am J Med. 1983;75(1a):40-5.

Yao X, Ye F, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of SARS-CoV-2. Clin Infect Dis. 2020.

Chen Z, Hu J, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv. 2020. **PREPRINT

Chen J, Liu L, et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19. J Zhejiang Univ (Med Sci). 2020;49(1):0-.

Gautret P, Lagier JC, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020:105949.

Coomes EA, Haghbayan H. Interleukin-6 in COVID-19: A Systematic Review and Meta-Analysis. medRxiv. 2020:2020.03.30.20048058. **PREPRINT

Savarino A, Boelaert JR, et al. Effects of chloroquine on viral infections: an old drug against today’s diseases? Lancet Infect Dis. 2003;3(11):722-7.

Kawasaki’s Disease

Cite this article as:
Alyssa Courtney. Kawasaki’s Disease, Don't Forget the Bubbles, 2017. Available at:
https://doi.org/10.31440/DFTB.12282
A four-year-old Japanese boy was brought into Emergency with 5 days of fevers, non-exudative bilaterally injected sclerae, erythematous pharynx and irritability.

Wondering about the possibility of Kawasaki Disease, I turned to check the 2017 update of the American Heart Association Scientific Statement, focusing on considering a diagnosis of Incomplete Kawasaki Disease.

 

Bottom line:

  • Unchanged diagnostic criteria of complete Kawasaki Disease (KD)
  • Refined algorithm for evaluation of suspected incomplete KD (15-20% of cases)
  • Recommended ECHO at diagnosis, and repeated at 1-2 weeks and 4-6 weeks after treatment
  • Unchanged acute management– Intravenous immunoglobulin (IVIG) single dose 2g/kg over 10-12 hours. Ideally prior to day 10. Some countries continue to use high dose aspirin for varying durations.
  • Additional therapeutic options are outlined for the 10-20% with persistent or recurrent fever
  • New model of KD vasculopathy

 

What is Kawasaki Disease?

An acute, self-limited febrile illness of unknown cause, predominantly in children <5 years. It is the most common cause of acquired heart disease in developed countries. Without pathognomonic tests, we need to detect it clinically!

 

Epidemiology

  • Most common in Japan (where it was first described) with an annual incidence of 264.8 per 100 000 children in 2012. The estimated incidence in North America is 25 cases per 100 000 children <5 years of age per year. Australia has one of the lowest reported rates (3.7 per 100 000 <5 years of age), equivalent to 50–60 cases Australia-wide per year. It is likely that the current Australian incidence is higher.
  • Highest relative risk is in Asian children, especially of Japanese ancestry
  • The ratio of males to females is 1.5:1
  • Predominantly affects children 6 months to 4 years
  • Predisposing factors have been reported inconsistently
  • In Japan, the recurrence rate is 3%, and the relative risk in siblings is ten-fold higher

 

What is the aetiology?

We have no idea why…. BUT the resultant systemic inflammation leads to associated clinical findings: liver (hepatitis), lung (interstitial pneumonitis), gastrointestinal tract (abdominal pain, vomiting, diarrhoea, gallbladder hydrops), meninges (aseptic meningitis, irritability), heart (myocarditis, pericarditis, valvulitis), urinary tract (pyuria), pancreas (pancreatitis), and lymph nodes (lymphadenopathy).

A new model of Kawasaki disease vasculopathy involves three processes impacting muscular arteries. The first is a necrotising arteritis, followed by subacute/chronic vasculitis. The final process is luminal myofibroblastic proliferation.

 

How do we diagnose it in Australia?

Diagnostic Criteria

Fever for 5 days or more (typically high spiking (>39°C to 40°C) and remittent)

Plus 4/5 of:

  • polymorphous rash (usually within 5 days of fever onset)
  • bilateral (non-purulent) conjunctival injection (usually begins shortly after fever onset and often spares the limbus, an avascular zone around the iris)
  • mucous membrane changes e.g. reddened or dry cracked lips, strawberry tongue, diffuse redness of oral or pharyngeal mucosa (oral ulcers and pharyngeal exudates are not consistent with KD)
  • peripheral changes, e.g. erythema of the palms or soles, oedema of the hands or feet, and in convalescence desquamation
  • cervical lymphadenopathy (> 15 mm diameter, usually unilateral, single, non-purulent and painful in the anterior cervical chain)

AND exclusion of diseases with a similar presentation

  • Staphylococcal infection (e.g. scalded skin syndrome, toxic shock syndrome)
  • Streptococcal infection (e.g. scarlet fever, toxic shock-like syndrome not just isolation from throat)
  • Measles
  • Viral exanthems
  • Steven’s Johnson syndrome
  • Drug reactions
  • Juvenile rheumatoid arthritis.

Trickily, these children may have a concurrent viral infection, often adenovirus. Adenovirus is more likely with exudative pharyngitis and conjunctivitis and positive PCR assay. Kawasaki disease is more likely with erythema/swelling of hands and feet, a strawberry tongue, and a desquamating groin rash.

Inflammation and crusting of a recent Bacille-Calmette-Guérin (BCG) injection site may occur.

Consider an alternative diagnosis to Kawasaki Disease if there is exudative conjunctivitis, exudative pharyngitis, ulcerative intraoral lesions, bullous or vesicular rash, generalized adenopathy, or splenomegaly.

 

What is Incomplete Kawasaki Disease?

Scarily, this is so easily missed. They make up 15-20% of all cases!!
Patients with incomplete KD, particularly those <6 months of age and older children, may experience significant delays in diagnosis and these children are at high risk of developing coronary artery abnormalities.

Consider KD if:

  • Infants <6 months old with prolonged fever and irritability
  • Infants with prolonged fever and unexplained aseptic meningitis
  • Infants or children with prolonged fever and unexplained or culture-negative shock
  • Infants or children with prolonged fever and cervical lymphadenitis unresponsive to antibiotic therapy
  • Infants or children with prolonged fever and retropharyngeal oroparapharyngeal phlegmon unresponsive to antibiotic therapy

Evaluation of suspected incomplete Kawasaki disease (via McCrindle BW et al. 2017)

What can we investigate?

As suggested by RCH Melbourne guidelines, all patients should have

  • ASOT / Anti DNAase B
  • Echocardiography (at least twice: at initial presentation and, if negative, again at 6 – 8 weeks).
  • Platelet count (marked thrombocytosis common in the second week of illness)
  • Consider Mycoplasma

In addition, findings can provide support when considering Incomplete Kawasaki Disease – refer to the above algorithm.

Evolution of laboratory findings via Tremoulet et al.

  • KD is unlikely if ESR, CRP, and platelet count are normal after day 7 of illness.
  • Low WBC and lymphocyte predominance suggests an alternative diagnosis
  • Leukocytosis is typical in the acute stage, with granulocyte predominance
  • Normocytic, normochromic anaemia is common during inflammation
  • CRP and ESR elevation is nearly universal, CRP normalizes more quickly with inflammation resolution. ESR is elevated by IVIG therapy.
  • Minimally elevated ESR in the setting of severe clinical disease should prompt investigation for disseminated intravascular coagulation.
  • Thrombocytosis is a characteristic feature that generally doesn’t occur until the second week, peaking in the third week, normalizing by 4 to 6 weeks
  • Thrombocytopenia can be a sign of disseminated intravascular coagulation and is a risk factor for the development of coronary artery abnormalities
  • Mild to moderate elevations in serum transaminases or gammaglutamyl transpeptidase occur in 40% to 60% of patients, and mild hyperbilirubinemia occurs in ≈10%.
  • Hypoalbuminaemia is common and associated with more severe and more prolonged acute disease
  • Urinalysis may show pyuria in up to 80% of children, non-specific for KD
  • In children who undergo lumbar puncture, ≈30% demonstrate pleocytosis with a mononuclear cell predominance, normal glucose levels, and generally normal protein levels

 

Pitfalls

Fever and pyuria in an infant or young child may be diagnosed as a urinary tract infection, with subsequent development of rash, red eyes, and red lips attributed to an antibiotic reaction. Irritability and a culture-negative pleocytosis of the cerebrospinal fluid in an infant with prolonged fever suggestive of aseptic meningitis (or if antibiotics have been given, partially treated meningitis) may cause a diagnosis of KD to be overlooked. Cervical lymphadenitis as the primary clinical manifestation can be misdiagnosed as having bacterial adenitis. Gastrointestinal symptoms are considered for surgical causes, other physical findings of KD can be overlooked.

 

What is the treatment?

We’re aiming to prevent important coronary artery abnormalities. Timely (as soon as possible, ideally within 10 days) IVIG treatment reduces the incidence of coronary artery aneurysms (defined from absolute luminal dimensions) from 25% to 4%. Studies with additional therapies to IVIG have not substantially reduced this residual risk of 4%. Adverse effects are rare but include Coomb’s positive haemolytic anaemia and aseptic meningitis. The measles, mumps, and varicella vaccine should be deferred for 11 months unless at high risk (seek advice, may need repeat vaccination). If the diagnosis is delayed, IVIG should still be given (after the tenth day of illness) IF there is presence of fever, or continued elevation of ESR or CRP>3, indicating ongoing inflammation. Aspirin is used with the theoretical rationale of reducing coronary artery aneurysms (although there is no well-established evidence for this). In Australia, a dose of 3-5mg/kg daily from diagnosis until cardiology review at 6 weeks is routine. The newly released statement advises the administration of moderate to high-dose (80–100 mg/kg/day) aspirin is reasonable until the patient is afebrile. Patients should receive a seasonal influenza vaccination.

Fever usually resolves within 36 hours after IVIG infusion has been completed; if not, the patient is considered to have resistance to IVIG. 10-20% of patients will not respond to the single IVIG treatment dose. There is minimal data to support therapeutic agents for the child with IVIG resistance. Repeating the IVIG dose, 3 days of high-dose pulsed steroids, or 2-3 weeks of tapering prednisolone are all options. There are lower levels of evidence for infliximab and cyclosporine.

 

Coronary artery abnormalities

An angiographic study of 1100 patients showed coronary artery lesions in 24%, with aneurysms in 8% and a number of patients with stenoses and occlusions. Valvular regurgitation is usually mild to moderate in severity and resolves prior to follow-up. MR can occur after the acute stage from myocardial ischaemia. Patients after KD have been shown to have functional and anatomic abnormalities of the aorta with unknown long-term implications. Myocarditis is common during the acute illness but complete resolution is expected. Risk stratification for long-term management is based primarily on maximal coronary artery luminal dimensions, normalized as Z scores, and is calibrated to both past and current involvement. Patients with aneurysms require life-long and uninterrupted cardiology follow-up.

 

What is the prognosis?

  1. The case fatality rate is <0.1% in Japan, virtually all from cardiac sequelae.
  2. Peak mortality occurs 15 to 45 days after onset of fever, during which time well-established coronary artery vasculitis occurs concomitantly with marked elevation of the platelet count and a hypercoagulable state
  3. Coronary artery aneurysms from KD account for 5% of acute coronary syndromes (ACS) in adults <40 years of age

 

In Summary:

  • Be aware of the diagnostic criteria of complete Kawasaki Disease (KD)
  • Highest relative risk in Asian children, especially Japanese ancestry
  • Always consider incomplete KD (15-20% of cases) and refer to the algorithm if concerns, there are pitfalls!
  • Liaise with cardiology regarding an ECHO
  • Unchanged acute management– Intravenous immunoglobulin (IVIG) single dose 2g/kg over 10-12 hours. Ideally prior to day 10. Some countries continue to use high dose aspirin for varying durations.
  • Additional therapeutic options are outlined for the 10-20% with persistent or recurrent fever, minimal evidence for these
  • New model of KD vasculopathy but we are still in the dark regarding aetiology
  • Coronary artery aneurysms from KD account for approximately 5% of acute coronary syndromes (ACS) in adults <40 years of age

 

 Selected references

McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. Circulation2017;Mar 29

Yim D, Curtis N, Cheung M, Burgner D. Update on Kawasaki disease: Epidemiology, aetiology and pathogenesis. Journal of Paediatrics and Child Health 49 (2013) 704–708

Clinical Practice Guidelines, Royal Children’s Hospital, Melbourne

Kim DS, Kawasaki Disease. Yonsei Medical Journal. 47 (2006) (6): 759–72. PMC 2687814 PMID 17191303. doi:10.3349/ymj.2006.47.6.759

Yim D, Curtis N, Cheung M, Burgner D. An update on Kawasaki disease II: Clinical features, diagnosis, treatment and outcomes. Journal of Paediatrics and Child Health 49 (2013) 614–623

Tremoulet AH, Jain S, Chandrasekar D, Sun X, Sato Y, Burns JC. Evolution of laboratory values in patients with Kawasaki disease. Pediatr Infect Dis J. 2011;30:1022–1026

Dengler LD, Capparelli EV, Bastian JF, Bradley DJ, Glode MP, Santa S, Newburger JW, Baker AL, Matsubara T, Burns JC. Cerebrospinal fluid profile in patients with acute Kawasaki disease. Pediatr Infect Dis J. 1998;17:478–481