Chloroquine and Hydroxychloroquine Toxicity

Etiology

Chloroquine and hydroxychloroquine bind to melanin in the retinal pigment epithelium (RPE) and cause damage to the macular cones outside of the fovea. The drugs inhibit the lysosome activity and reduce phagocytosis of shed photoreceptor outer segments causing an accumulation. In response, pigment-containing RPE cells migrate into the outer nuclear and outer plexiform layers of the retina, resulting in irreversible photoreceptor loss and RPE atrophy.[5] HCQ has a long half-life and takes about 6 months to achieve full elimination from the body. This is clinically significant when managing side effects such as retinal toxicity and explains continued maculopathy even after discontinuation of the medication. Corneal deposits result from binding to cellular lipids and deposition of the drug in the basal epithelial layer of the cornea. Discontinuation of the drug usually causes the deposits to disappear over time. 

Chloroquine is completely absorbed when taken orally and accumulates in various tissues.[6][7] After ingestion, chloroquine causes transiently high levels in the blood compartment before redistributing into the tissues. This high level in the blood compartment is what causes cardiac toxicity, hemodynamic instability, and collapse in acute overdoses. Both chloroquine and hydroxychloroquine are known to cause significant sodium and potassium channel blockade, resulting in QRS and QT prolongation, as well as cardiac arrhythmias in acute toxicity.[8]

Epidemiology

The incidence of retinal toxicity with chronic use of hydroxychloroquine was found to be 0.38% in a 2003 study of 526 patients and as high as 0.68% in a study conducted in 2010 in which the subjects used the medication for 5 to 7 years.[9] Based on this study, the American Academy of Ophthalmology recommended new screening guidelines in 2011. The same study revealed that the most important predictor of chronic ocular toxicity was the duration of use (cumulative dose), age, the daily dose, and patient weight did not correlate significantly with hydroxychloroquine toxicity. Another study revealed a much higher overall risk of 7.5% retinal toxicity among the 2361 patients studied.[10] This study also found that kidney disease and tamoxifen therapy increased the risk of retinopathy. A report in 2015 described that pericentral maculopathy without the classic parafoveal retinopathy was more common in Asian patients (50%) compared to Caucasian patients (2%), and Asian patients should receive adapted screening tests such as wider angle threshold visual field tests.[11]

During the initial period of the COVID-19 pandemic, hydroxychloroquine was being used off-label for the treatment of this novel respiratory virus. As a result, there was an increased incidence of cardiac toxicity, including QT prolongation, torsades de pointes, and cardiac arrest, documented in the literature.[12] Ocular adverse effects are most commonly seen with chronic use. Due to the shorter duration of therapy used to treat Covid 19, ocular toxicity was not a clinically significant problem.[13][14] Gastrointestinal side effects are another common side effect of hydroxychloroquine and chloroquine use. These side effects are seen even with short duration of therapy.[15] Chloroquine overdoses are rare in the United States but much more common in areas of the world where malaria is endemic.

Pathophysiology

In malaria, chloroquine and hydroxychloroquine act as chemotherapeutic agents against erythrocytic forms of the Plasmodium parasites. Absorption of the drug increases the pH of the acidic food vacuoles of the parasite, which interferes with the reproduction of the parasite.[16] The drugs also inhibit parasite growth by interfering with the conversion of toxic heme, released from the parasite digestion of hemoglobin to the nontoxic hemozoin.[17]  As a treatment for rheumatic disease, hydroxychloroquine and chloroquine increase the pH in the lysosomes of antigen-presenting cells and inhibit toll-like receptors (TLR) function on dendritic cells. It also reduces the activation of these cells and reduces inflammation by inhibiting the production of pro-inflammatory cytokines. [3] These drugs also accumulate in white blood cells and, by stabilizing lysosomal membranes, inhibit the activity of enzymes that cause cartilage breakdown, such as collagenase and protease. TLR 9 recognizes DNA-containing immune complexes, and inhibition by CQ/HCQ leads to inhibition of anti-DNA auto-inflammatory processes, such as in SLE.[18]

HCQ and CQ are structurally similar to quinine and cause similar cardiovascular conduction effects. Hypokalemia occurs more commonly in chloroquine use. This is a result of intracellular shift rather than a true potassium deficit.[19][6] Chloroquine has a small therapeutic window, and ingestions of 5 grams or more result in significant toxicity defined as wide QRS complexes, ventricular fibrillation, and hypokalemia.[20][21] Hypotension secondary to decreased cardiac contractility and respiratory depression are also common in these overdoses.[22] CNS depression and seizures have also been reported. It is critically important for providers to remember that chloroquine and hydroxychloroquine can cause significant hemolysis in patients with G6PD deficiency. 

Histopathology

SD-OCT testing visualizes the retinal layers in as much detail as microscopic examination. In CQ/HCQ retinopathy, a loss of photoreceptor inner-outer segment junction (the ellipsoid zone or the photoreceptor integrity line (PIL)) and a thinning of the outer nuclear layer of the retina are observed.[23]

Toxicokinetics

Both chloroquine and hydroxychloroquine have excellent oral absorption and bioavailability. They have a long elimination half-life and a large volume of distribution. In overdose, significant toxicity occurs rapidly and can be expected within 1-3 hours after ingestion.[21]  Both medications have a long and variable plasma elimination half-life because of a high volume of distribution, and about 65-70% of drug metabolites are renally excreted. Both drugs are hepatically metabolized by the hepatic cytochrome P450.[24] Chloroquine and hydroxychloroquine readily cross the placenta by passive diffusion with strong correlations between maternal and fetal concentrations.[25] However, it is used therapeutically and has been shown to be safe for use in pregnancy.[26] HCQ and CQ are also excreted in breast milk. 

History and Physical

An ocular history should include specific questions regarding any preexisting retinal disease. Additionally, questions about central acuity and the ability to focus on near objects and glare should be asked. Common nonocular adverse effects of CQ and HCQ include pruritus, headaches, dizziness, and gastrointestinal upset, which should be asked about as they can lead to medication noncompliance. HCQ myopathy is uncommon but can present with proximal muscle weakness. In these cases, a muscle biopsy can determine characteristic pathologic findings.[27]

History concerning acute toxicity should include the medical conditions that prompted CQ or HCQ therapy, the time since the last prescription refill, the time of ingestion, the daily dose, and the quantity ingested. In suicidal patients, who are often not forthcoming, or in critically ill overdose patients with CNS depression, a comprehensive medication review may lead an emergency physician or medical toxicologist to the possibility of HCQ/CQ as the most likely ingestion. In addition, the presence of significant vital signs abnormalities and EKG conduction abnormalities may also indicate an acute overdose. The physical exam may demonstrate CNS or respiratory depression but is not specific to the toxicity of HCQ and CQ. 

Evaluation

Three reports from the American Academy of Ophthalmology in 2002, 2011, and again in 2016 have provided clinicians with evidence-based guidelines for screening patients on CQ/HCQ therapy.[28] Baseline testing within the first year of starting therapy should include a dilated fundus exam to document pre-existing retinal pathology. While the latest recommendations do not require it, automated visual field (VF) testing and spectral domain optical coherence tomography (SD-OCT) are also often done at this visit. Guidelines recommend a 10-2 threshold VF except for Asian patients, where a wider angle test such as a 24-2 or 30-2 VF protocol will pick up the 50% that develop retinopathy outside the central 20 degrees of VF. Additional recommended screening tests include SD-OCT, fundus autofluorescence (FAF), and the most sensitive test of all, multifocal electroretinography (mf-ERG). For Asian patients, wide-field SD-OCT and FAF should be performed. Tests no longer recommended include baseline retinal photography, time-domain OCT, full-field ERG, electro-oculography, fluorescein angiography, color vision, and Amsler grid tests.

The guidelines recommend starting annual screening after 5 years unless additional risk factors include small stature, obesity, liver or kidney disease, and retinal disease. In these cases, test on an annual basis from the start. Since mf-ERG is the most sensitive test but is not as readily available, some protocols recommend introducing it at a later stage.[28] These guidelines recommend doing SD-OCT/FAF and VF tests first and introducing mf-ERG only when these tests suggest retinopathy.

Interpretation of Results

• Visual field: Defects are most likely to occur at 5 degrees from the center, except in Asian patients where the defect may be over 10 degrees from the center. Use statistical analysis to determine the significance of the data.
• SD-OCT: will reveal parafoveal thinning of the photoreceptor integrity line and the outer nuclear layer of the retina; this results in a "flattening" of the foveal depression and the "flying saucer sign" where the outer nuclear layer in the fovea's center is unaffected, and just around it this layer is much thinner (the edge of the saucer).
• FAF: reveals in early maculopathy a ring of hyperfluorescence (caused by the accumulation of lipofuscin) and, in later stages, a ring of hypofluoresence (caused by the loss of photoreceptor and retinal pigment epithelial layers).[29] 
• mf-ERG: amplitude reduction is most common in ring 2, followed by rings 3, 4, and 1. Delayed implicit times are less common.[29]
• The dilated fundus exam: 2016 recommendations indicate that end-stage bull's eye maculopathy presents less often with better dosing guidelines and earlier detection. However, the clinician should have familiarity with the fundus appearance of irregularity in the macular pigmentation in the early phase, a ring of macular pigment dropout in the advanced stage, and peripheral bone spicule formation, vascular attenuation, and optic disc pallor in the end-stage.   

Acute Toxicity

The evaluation of a known or suspected hydroxychloroquine or chloroquine overdose should include a comprehensive approach, including the following:

• Laboratory studies
  • Point of care glucose to assess for hypoglycemia
  • Complete blood count to assess for hematologic abnormalities
  • Comprehensive metabolic panel to assess for electrolyte abnormalities- in particular, hypokalemia, as well as renal function and hepatic function
  • Acetaminophen and salicylate levels to rule out coingestions 
• EKG and continuous cardiac monitoring to assess for cardiac conduction abnormalities and arrhythmias 

Treatment / Management

Convincing evidence of chronic toxicity should result in the drug's discontinuation in consultation with the prescribing physician. Because of the long half-life of both drugs, retinopathy can continue for over 6 months, and studies have shown ongoing changes for up to 20 years after cessation of the drugs.[30] The goal is to detect early indications of retinal toxicity while the patient is still asymptomatic.(B3)

In acute overdoses, aggressive supportive care, including IV access, oxygen, telemetry, and blood pressure monitoring, are critical to the management of chloroquine or hydroxychloroquine acute toxicity. In addition, gastric lavage and activated charcoal should be considered for gastrointestinal decontamination in treating these patients, especially in the time frame soon after ingestion. Activated charcoal has been shown to bind well to hydroxychloroquine when administered soon after ingestion.[31] Careful consideration must be given to the potential CNS depression, hemodynamic collapse, and the incidence of seizures before any gastrointestinal decontamination is initiated. Early and aggressive management of severe overdoses, including endotracheal intubation, has been shown to decrease mortality.[32] Barbiturates have been associated with cardiac arrest when used for induction during intubation and should be avoided. (B3)

In the setting of hemodynamic instability, epinephrine has been the most studied vasopressor and is recommended for use in both chloroquine and hydroxychloroquine toxicity in doses of 0.24 µg/kg/min.[33] In conjunction with high doses of diazepam (1-2mg/kg/d), epinephrine has been shown to decrease mortality. Initial observations in patients with co-ingestions of chloroquine as well as diazepam showed decreased cardiac toxicity and a potential benefit of diazepam administration.[20][19] Animal studies and human reports later replicated this conclusion. There was a dramatic decrease in mortality shown when patients were treated with high-dose diazepam, epinephrine, and mechanical ventilation, with survival rates of 91% vs 9% without.[21] Although there has been speculation as to the possible mechanism for the benefit of diazepam use in chloroquine toxicity, it is unclear exactly how it works.[34](A1)

While sodium bicarbonate is typically used to treat toxicity secondary to sodium channel blockade, it is not routinely recommended in the treatment of chloroquine and hydroxychloroquine toxicity. Concomitant hypokalemia, as well as QT prolongation, should be considered before initiating sodium bicarbonate for treatment.[35](B3)

Differential Diagnosis

Differential Diagnosis for CQ/HCQ Vortex Keratopathy (VK, also called corneal verticillata)

• Subepithelial deposition of other medications: A good medical history should reveal the medication responsible. Amiodarone is most commonly the cause of vortex keratopathy, followed by CQ, HCQ, indomethacin, and phenothiazines. The appearance of the verticillata caused by these different medications is similar in appearance.[36]
• Fabry disease: Verticillata from Fabry disease is similar in appearance to those caused by medications. Fabry disease presents with retinal vessel tortuosity and cataracts as well. Other findings include pain in the extremities and angiokeratomas of the skin. Cardiovascular, renal, and cerebrovascular disease are late manifestations.[37]
• Iron lines: Caused by iron deposition from the tear film into the basal epithelium layer.[38]
• Hudson Stahli line: Tends to be more linear and usually horizontal and at the junction of the lower one-third and upper two-thirds of the cornea.
• Fleisher ring: This is present in moderate to advanced cases of keratoconus. The inferior portion of the ring may be present in less advanced cases and can be confused with VK.
• Corneal irregularity from refractive procedures such as radial keratotomy:  The deposits are within the irregularities caused by the surgery (for example, within the radial keratotomy incisions).
• Stocker's line: The iron line is found next to the head of a pterygium.
• Ferry's line: The iron line is found next to a glaucoma filtering bleb.
• Gout: Uric acid crystal deposition in Bowman's membrane appears as a dust-like brown type of band keratopathy. In an early stage, it can be confused with VK.[39]
• Corneal chrysiasis: Caused by deposition of gold in the corneal stroma. A good medical history should reveal treatment history with intramuscular injections of gold salts. The deposition is more granular in appearance and more diffusely distributed throughout the surface of the cornea.[40]

The Differential for CQ/HCQ Retinopathy

Age-related macular degeneration: Geographic atrophy (GA) in the absence of drusen and choroidal neovascularization and CQ/HCQ retinopathy can present similarly. Both present with thinning of the photoreceptor integrity line and the outer nuclear layer of the retina and atrophy of the choriocapillaris on SD-OCT.[41]  However, GA does not appear in a parafoveal ring (bull's eye) pattern. Conversely, especially in Asian patients, CQ/HCQ retinopathy does not present in the typical bull's eye pattern either, and the clinician will need to use other clinical criteria to differentiate the two conditions. One study revealed that reticular drusen are visualized in all patients with GA by SD-OCT and FAF, and their presence can be a valuable tool to differentiate GA from CQ/HCQ retinopathy.[42]  mf-ERG reveals a typical paracentral reduction in CQ/HCQ retinopathy that is not present in GA. 

Central areolar choroidal dystrophy (CACD): CACD can appear in a bull's eye pattern. However, it develops between age 20-40 years old, usually too young of an age to have been on CQ/HCQ for over 20 years and to be at high risk of CQ/HCQ retinopathy. It progresses through 4 stages, each associated with characteristic retinal and choroidal findings. A speckled FAF pattern is present in 85% of patients with CACD and can be used to differentiate CACD from GA and CQ/HCQ retinopathy.[42]

Stargardt disease: The presence of irregular, pisciform, yellow flecks at the RPE level in the macula with a possible extension into the periphery differentiates Stargardt disease from CQ/HCQ maculopathy. The most typical age of onset is in the 2nd decade of life; the classic "beaten bronze" appearance and positive genetic testing for the ABCA4 mutation are additional ways to differentiate the two conditions. Finally, the classic "silent choroid" found in patients with Stargardt disease when tested with fluorescein angiography is absent in patients with CQ/HCQ retinopathy.[43] Conversely, a recent study of eight patients with Stargardt disease revealed an almost complete overlap of SD-OCT, FAF, mf-ERG, and fundus findings with CQ/HCQ retinopathy.[44]

Cone-rod dystrophy (CRD): CRD can present with bull's eye maculopathy. CRD occurs in childhood and causes loss of central vision and photophobia in the early stage, followed by central scotomas, loss of color vision, and peripheral vision. Night blindness is present in the early stage. Photopic and scotopic ERG testing precisely differentiates CRD from CQ/HCQ retinopathy.[45]

Benign concentric annular dystrophy (BCAD): This rare disorder is characterized by a bull's eye macular pigmentary change while visual acuity is well-preserved.[46]

Differential Diagnoses for Acute Toxicity Include Xenobiotics

• Beta-blockers (metoprolol, propranolol, sotalol, etc): In addition to hypotension and cardiac conduction abnormalities, beta blockers typically will cause concomitant bradycardia and may be associated with hypoglycemia. Glucagon is often the initial intervention recommended but will only have transient effects and is of no long-term benefit in managing patients with significant toxicity. High-dose euglycemic insulin therapy and vasopressors in consultation with a medical toxicologist or poison control center are essential in the management of these patients but contraindicated in HCQ and CQ toxicity. 

• Calcium channel blockers (verapamil, diltiazem, amlodipine, etc): Similar to beta blockers, calcium channel blockers cause bradycardia, conduction abnormalities, and hypotension. It is important to remember that in the initial period after a dihydropyridine overdose, patients may have transient tachycardia secondary to peripheral vasodilation. Patients will typically develop bradycardia after that initial period. Finally, hyperglycemia is unique to calcium channel blocker overdoses, and the presence of hyperglycemia may lead providers down a treatment pathway specific to these medications. Beware that diabetic patients can also have hyperglycemia unrelated to toxicity. High-dose euglycemic insulin therapy is the indicated treatment for this toxicity but is again contraindicated in HCQ/CQ toxicity. 

• Loperamide: Loperamide is an antidiarrheal with opioid effects typically abused in patients with opioid use disorder. This medication can cause both QRS and QT prolongation with significant cardiac abnormalities, including wide complex ventricular arrhythmia and torsades de pointes. Patients may present with syncope and abnormal EKGs as well as altered mental status. This toxicity is primarily managed with supportive care, but similar to HCQ/CQ, caution should be used when using sodium bicarbonate for dysrhythmias because it can worsen hypokalemia and worsen QT prolongation. 

• Clonidine: Clonidine is an alpha-2 adrenergic agonist that causes bradycardia and hypotension. This drug causes a clinical picture similar to opioid toxicity with CNS depression and miosis. Supportive care, including intravenous fluids and the use of vasopressors, is the mainstay of treatment in clinically significant overdoses. 

• Quinine: Quinine has the most similar presentation to CQ and HCQ overdoses and often has associated hypokalemia. This ingestion is more often accompanied by hypoglycemia than HCQ/CQ. Severe HCQ and CQ overdoses can also cause significant hypoglycemia. 

Toxicity and Adverse Effect Management

Mortality of hydroxychloroquine and chloroquine overdoses is estimated between 10-30% but may be higher. Aggressive management of acute overdose and toxicity is critical to the survival of the patient. 

Initial management should include epinephrine for vasopressor support and correction of any electrolyte abnormalities, with particular attention to hypokalemia, which commonly accompanies these overdoses. Hypoglycemia should also be managed appropriately with boluses and continuous infusions of intravenous dextrose as needed. 

Patients with significant hemodynamic collapse should be intubated and sedated with high-dose diazepam infusions.[19] In addition, clinicians should consider GI decontamination with activated charcoal if not contraindicated and gastric lavage depending on the time of ingestion, quantity ingested, and clinical presentation.[47][48]

Hemodialysis is not currently indicated or recommended in the management of hydroxychloroquine or chloroquine toxicity.[49] Of note, ophthalmic manifestations of toxicity are not typically seen in acute overdoses.[22] Vision and hearing changes are much more commonly seen with chronic use and tend to be irreversible.[50]

Prognosis

When the clinician who detects early retinopathy does not discontinue CQ/HCQ therapy, the prognosis is a progressive loss of paracentral vision followed by loss of central vision and night blindness. Even when the clinician discontinues therapy, retinopathy can progress for years after. Progression of vortex keratopathy causes increasing haloes and blur but is fully reversible upon discontinuation of therapy. 

The prognosis in the setting of acute chloroquine and hydroxychloroquine overdoses depends on the quantity ingested. There have been pediatric deaths after ingesting as little as 1 to 2 tablets. It is estimated that 2 to 3 times the therapeutic dose can be fatal in less than three hours. Ingestions of 8 to 22g have caused life-threatening toxicity in adult patients. 

Complications

Even when the clinician and patient adhere to screening guidelines with chronic use, discontinuing chloroquine or hydroxychloroquine therapy may not stop the progression of retinopathy to a stage where the patient's vision is spared. 

In acute ingestions, toxicity can be complicated by multiorgan failure and death, secondary to hemodynamic collapse. Patients may have prolonged and irreversible effects long after the acute toxicity has passed.