COVID-19: Considerations for Treatments Using Quinine Derivatives and Other Ototoxic Compounds

In recognition of May Is Better Hearing Month…consider these options for yourself and your patients in this challenging and uncertain time.

Hydroxychloroquine was recently approved by the U.S. Food and Drug Administration (FDA) for emergency use to treat adults and adolescents with COVID-19.

Research supporting use of these agents for treatment of COVID-19 is currently limited to a few small samples with contradictory findings. In addition, optimal dosing strategies remain unknown. The FDA has released a fact sheet to help understand the findings.

Chloroquine and hydroxychloroquine are synthetic derivatives of quinine. Quinine and its derivatives have a long history as anti-malarial and for treatment of autoimmune disorders such as lupus and rheumatoid arthritis. Review the historical commentary.

For Audiologists

Quinine is considered a standard potassium (K+) channel blocker. In isolated outer hair cells (OHCs), application of quinine results in a sustained hyperpolarization of the OHC. This means the OHC remains elongated, which then reduces the active force of the OHC motility. The effect of quinine is not likely limited to the OHC, rather it appears that quinine alters the mechanoelectric transducer (MET) of hair cells and interferes with K+ recycling, notably intermediate cells (melanocytes) of the stria vascularis. It is worth noting that cholorquine and hydroxychloroquine have similar mechanisms, but the incidence of ototoxicity is considered much lower.

In comparison, salicylate also creates a temporary hearing impairment, and the primary target appears to be the OHC. However, it is the negative charge of salicylate that acts as a competitive antagonist against chloride at the binding site for prestin that appears to underlie its mechanism.

Alvan et al (2016) provide an excellent study on the dose relationship and molecular mechanisms.

A recent review of hydrochloroquine ototoxicity in France revealed 22 cases; however, most only developed hearing loss after months or years of treatment, which is longer than in COVID-19 treated patients (Chatelet et al. 2017). Of the 5 patients that developed symptoms within 14 days, hearing loss was associated with tinnitus, vertigo or imbalance and in one case headache.

All otologic symptoms except in one patient resolved after cessation of the therapy. The cases of irreversible sensorineural hearing loss associated with hydroxychloroquine and chloroquine were in patients who had treatment over several years (Bortoli and Santiago 2007; Johansen and Gran, 1998).

Severity of hearing loss, tinnitus, and balance deficits will be influenced by dose, duration of use, and patient factors. In general, the effects appear to be transient in nature with severities of hearing loss reach >50 dB threshold shift, still showing full recovery. Concern is warranted for inclusion of additional ototoxic compounds and insults such as noise exposure. Though, quinine-based drugs have been used as a treatment to prevent other ototoxicity from aminoglycosides and cisplatin. Use in pregnant women should also be cautioned for potential birth defects including increased risk for hearing loss.

Another consideration is use of chloroquine and azithromycin. Azithromycin has low-level ototoxic properties, and a recent analysis found no ototoxic effects in short duration use (Alrwisan et al, 2018).

How to Screen for Ototoxicity when Social Distancing

It is more than likely patients will not have a baseline audiogram and facilities will not have the time or resources to conduct these evaluations. Simple questions can be used to determine baseline status and monitor hearing and balance.

Baseline: Currently

• Do you have difficulty hearing or known hearing loss?
• Do you have difficulty following conversation in a noisy environment?
• Do you hear ringing, buzzing, humming or similar sound without an external source?
• Do you have any dizziness, off-balance sensation or experience spinning sensations?

Monitor: Since starting hydroxychloroquine-

• Have your experienced a change in your hearing?
• Have you experienced a plugged-up ear feeling?
• Have you experienced ringing, buzzing, humming or other sound without an external source?
• Have you experienced a change in balance or spinning sensations?

For Patients

The hearing loss, tinnitus (perception of ringing, buzzing, humming without an external source), and balance effects of hydroxychloroquine/chloroquine are often only temporary in nature. The drug can create a transient change in the function of the inner ear. This change usually reverses once the treatment is discontinued.

For safety, limit your exposure to loud sounds and/or consistently use hearing protection when around loud sounds to reduce risk for hearing damage. It is possible that exposure to other ototoxic drugs (e.g. cisplatin, aminoglycosides, aspirin-based drugs, loop-diuretics) may increase risk for damage, but do not discontinue medications without first communicating with your physician.

Reduced hearing can be isolating and frustrating, but simple communication strategies can help.

1. Watch the speaker (of limited value if speaker is wearing a mask).
2. If you don’t understand, ask for clarification by repeating the information you heard.
3. Place yourself at a good distance, not too close and not too far; you should be able to see the speaker.
4. Be assertive: For example, ask for repetition, identify the part of the sentence you need repeated.
5. If you’re in a noisy room, suggest moving somewhere quieter, or turn off or down noise source (music, tv, etc.).
6. Turn your smartphone into an amplifier, check out the EarMachine App (must be used with headphones/earbuds).
7. Communication partners should use clear speech—a method where the speaker talks slightly slower and louder, uses frequent pauses, and enunciates speech sounds more clearly. It is not exaggerated speech, but rather a style of speaking that is adopted intuitively by many talkers in difficult communication situations. The communication partner should face the person with hearing loss, make sure their mouth can be seen (if possible), and rephrase when something is not understood.
8. Understand hearing loss can be frustrating for the patient and communication partner. Communication is a two-way street, both patient and communication partner are advised to try to remain calm and do the best you can.
9. Use of a protective mask may exacerbated communication errors due to attenuation of speech and loss of visual cues.

Tinnitus (ringing, buzzing, humming, etc) is a common side effect of change in sound input into the auditory system. When sound input to the brains is disrupted, it attempts to change to compensate.

The central gain and increase in neural activity to compensate can result in perception of a sound called tinnitus. This is known side effect of quinine-based drugs and is often only temporary. If you are having difficulty with your tinnitus here are some tips.

1. Understand the Source: Tinnitus is a common side effect of reduced sound to central parts of the auditory pathway; it is not a sign that you are going deaf or having a serious adverse reaction. This may be a side effect of hydroxychloroquine but is usually only temporary.
2. Habituation and Cognition: Your brain can learn to find the tinnitus less important and habituate to the sound. Habituation is a process where your brain determines if some type of stimulus is important or not. For example, a ring on your finger or watch on your wrist is touching you throughout the day and stimulating neural receptors. But most of the day your brain is filtering this signal and you do not actually feel those items. Yet, when you think about it, you can.

Your brain does this the same thing with external sounds. For example, the air conditioner (AC). You may notice the AC turn on because it is a new sound or change in your environment’s sound. However, shortly after the AC turning on, you go back to watching TV or reading and do not notice the AC again until it turns off. It makes sense if you find the tinnitus to be annoying and bothersome.

If you were driving your car down the road and heard a sudden grinding sound in the engine, your first thought would not be positive or that this is a good sign. Try to stay positive and understand that tinnitus is usually only temporary with hydroxychloroquine and chloroquine.

3. Use Sound: Sound enrichment can help reduce tinnitus. Keep a steady soothing sound in the background or played through some earphones. The sound does not need to be loud, just loud enough to provide some relief. Broadband sounds including white noise or pink noise and environmental sounds such as ocean or rain are commonly used.Also, you can also just have a fan on in the background. In the bedroom, consider ordering a Soundpillow or Dreampad; these are pillows that can deliver sounds to your ears to help you sleep. Even taking a shower can help ease tinnitus. There are many apps you can find on a smartphone that are free (e.g., Relax Melodies).
4. Attention: Just don’t think about the tinnitus. Well, it’s not that easy; tinnitus can be annoying and often persons with tinnitus can feel they have no control or can’t escape the tinnitus. However, this is false. Sound can help reduce how you perceive your tinnitus. So can attention. If you are bothered by your tinnitus, try not to focus on it. Do something to alter your attention, something positive and with sound. Put on your favorite movie, call-up a friend, go for a walk (if well enough). Do something positive to distract the brain from the tinnitus.
5. Sleep, Diet, and Activity: Sleep is critical. Use a nice soothing sound in the bedroom. Also follow sleep hygiene tips: make sure the temperature in the room is comfortable, have a comfortable pillow and sheets, etc. Eating healthy is important for your general health and well-being, this will not cure tinnitus but will also not hurt it. Staying active, not just physically but mentally can help reduce your brains attention to your tinnitus and keep you healthy.
6. Tinnitus associated with hydroxychloroquine is often only temporary. The tinnitus will likely resolve after your treatment. If not, contact your physician and an audiologist for further evaluation and management.

References

Alvan et al. (2016) Concentration-response relationship of hearing impairment caused by quinine and salicylate: Pharmacological similarities but different molecular mechanisms. Basic Clin Pharm and Tox 120:(1).

Alrwisan et al. (2018) Azithromycin and sensorineural hearing loss in adults: A retrospective cohort stud. Otol Neurotol 39(8):957–963.

Bortolim R, Santiago M. (2015) Chloroquine Ototoxicity. Clin Rheumatol 26(11):1809–1810.

Chatelet J, Auffret M, Combret S, BNondon-Guitton E, Lambert M Gautier S. (2017) Hydroxychloroquine-induced hearing loss. First case of positive rechallenge and analysis of the French pharmacovigilance database. Rev Med Interrie 38(5):3450–343

Johnasen PB and Gran JT. (1998) Ototoxicity due to hydroxychloroquine: Report of two cases. Clin Exp Rheumatol 16(4):472–474.

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