Chloroquine

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One nonrandomized study found that more hydroxychloroquine azithromycin patients tested negative for virus at days 3 and 6 but clinical outcomes were not reported.

One unblinded randomized trial showed no effect from hydroxychloroquine on viral or clinical outcomes. Without further evidence, hydroxychloroquine is not appropriate for patients with COVID-19 in primary care. 

McMaster Empendium

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EPIDEMIOLOGY

The first cases of coronavirus disease 2019 (COVID-19) occurred in China, with the highest number of reported cases to date, but the epidemic is spreading globally. Current epidemiologic data are available at www.who.intwww.cdc.gov, and www.ecdc.europa.eu.

ETIOLOGY AND PATHOGENESIS

1. Etiologic agent: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an RNA virus that belongs to the Betacoronavirus (betaCoV) genus. The genus also includes SARS-CoV, which was responsible for the epidemic in 2002 and 2003.

2. Pathogenesis: Not well understood. To enter the cell, the virus uses angiotensin-converting enzyme 2 (ACE2) as a receptor, binding to ACE2 using the spike glycoprotein on the viral envelope. In response to viral antigens, immune cells release proinflammatory cytokines and chemokines, which result in an uncontrolled systemic inflammatory response. This is one of the key mechanisms leading to the development of acute respiratory distress syndrome (ARDS).

3. Reservoir and transmission: An animal reservoir has not been clearly identified to date but the virus has most likely originated in bats. In the current epidemic the reservoir for SARS-CoV-2 is infected individuals.

Human-to-human transmission occurs by inhalation, primarily through large respiratory droplets. However, airborne transmission during aerosol-generating medical procedures and transmission by direct contact have not been excluded. Other transmission routes are under consideration. Transmission by contact is plausible and very likely, as with any respiratory virus. The virus may be also found in blood at the early stages of the disease, but transmission through blood has not been confirmed to date. The infection is spread by symptomatic individuals with COVID-19 and possibly by those with asymptomatic infection with SARS-CoV-2. A recent study found that under experimental conditions SARS-CoV-2 can remain viable in the air after aerosolization for ~3 hours and for longer time on surfaces like plastic, copper, and cardboard. Similarly, these findings were observed with SARS-CoV-1.

4. Risk factors for infection: Epidemiologic risk factors include a history of travel to epidemic areas, household contact with an infected person, provision of direct medical care for an infected patient, and sharing an enclosed space (eg, classroom, meeting room, waiting room in a hospital) with an infected individual. Transmission is enhanced by face-to-face or direct physical contact with an infected person (eg, handshake), contact with secretions of an infected person while not wearing protective equipment, handling of specimens collected from an infected person by laboratory personnel without adequate protective equipment, and likely travel by plane or other transportation modes in close proximity to a person infected with SARS-CoV-2. Prolonged contact increases the risk of infection. Risk factors for severe versus mild infection include advanced age (in patients aged ≥80 years mortality rates are reported to be up to 15%, although some mildly symptomatic patients may not be counted, thus increasing the observed risk), chronic respiratory disease, cardiovascular disease including hypertension, malignancy, diabetes mellitus, and immunosuppression.

5. Incubation and contagious period: The incubation period is usually from 2 to 14 days (5 days on average). Symptomatic individuals may transmit the virus to others; the extent of transmission from those who are presymptomatic—if such transmission in fact occurs—is unknown. Viral shedding is probably the highest ~10 days from the moment of infection; however, it may likely last longer in patients who develop severe infection. The duration of the contagious period is not clearly established. Patients with mild infection typically recover within 1 week or up to 2 weeks, while those with severe infection recover within 3 to 6 weeks.

CLINICAL and NATURAL HISTORY

The clinical course may be varied and ranges from asymptomatic/subclinical infection to severe pneumonia with ARDS:

1) Symptomatic uncomplicated infection: Patients have nonspecific manifestations, such as fever, cough, malaise, shortness of breath, myalgia, sore throat, and headache. No dehydration, dyspnea, or features of sepsis are seen. Elderly individuals and immunocompromised patients may have atypical symptoms.

2) Mild pneumonia: No features of severe pneumonia listed below are seen.

3) Severe pneumonia: Fever or other symptoms of respiratory tract infection with tachypnea >30/min or hemoglobin oxygen saturation in arterial blood (measured with pulse oximetry) (SpO2) on room air <90%.

4) ARDS occurs in up to 15% of hospitalized patients with COVID-19.

5) Sepsis and septic shock: The incidence of sepsis in patients with COVID-19 is not well described. The incidence of shock in published reports was highly variable, ranging between 2% and 20%.

In ~80% of diagnosed patients the course of disease is mild. Approximately 15% of patients develop severe infection with dyspnea and hypoxia, and within 24 to 48 hours radiographic features of pneumonia develop in >50% of these individuals. Approximately 5% of diagnosed patients become critically ill with acute respiratory failure, shock, and multiorgan dysfunction. Among critically ill patients with COVID-19, the mortality rate approaches 50%. In a described cohort of Italian patients, 16% of hospitalized patients required intensive care unit (ICU) admission. The overall mortality rates differ by country and demographic characteristics in a given report, and as of March 24, 2020, reached ~4% across the world (up to 9% in Italy). However, these mortality rates have a wide margin of error because there is likely an overrepresentation of severely ill patients in whom the infection has been confirmed, while many patients with mild infection would not have undergone testing and are therefore missing in the denominator.

DIAGNOSIS

Diagnostic Tests

1. Identification of the etiologic agent: The key diagnostic method is detection of genetic material from the virus using polymerase chain reaction (PCR) and real-time PCR (RT-PCR). The specimens of choice are specimens collected from the lower respiratory tract (only in intubated patients; endotracheal aspirates [ETAs] or bronchoalveolar lavage [BAL]), uninduced sputum, nasopharyngeal swabs, and nasopharyngeal aspirates. In the first week of disease blood samples may also be used; however, starting from the second week the results of blood tests may be negative even in patients with active infection.

2. Other tests:

1) Laboratory tests: Patients commonly have leukopenia and lymphopenia, but leukocytosis may also occur. Procalcitonin levels are usually normal but may be elevated in patients requiring admission to an ICU. Serum aminotransferase levels may be increased.

2) Radiography:

a) Chest radiography: Most frequently features of bilateral pneumonia.

b) Chest computed tomography (CT): Radiographic abnormalities can be seen early, even before symptom onset. They are usually bilateral, show peripheral distribution, and are more often located in the inferior lobes. Extensive ground-glass opacification can be seen especially in the second week of the disease, which progresses to a mixed pattern by week 3 or 4. Patients may also have pleural thickening, pleural effusion, and lymphadenopathy.

3) Monitoring involves monitoring of blood pressure and SpO2 and the quick sequential organ failure assessment (qSOFA)

Diagnostic Criteria

Case definitions for COVID-19 by the World Health Organization (WHO) (current as of March 13, 2020):

1) Suspected case of COVID-19: A patient with:

a) Fever and ≥1 signs or symptoms of respiratory disease (eg, cough, dyspnea) with no other etiology that fully explains the clinical presentation and with a history of travel to or residence in a country or area that reported local transmission of SARS-CoV-2 during the 14 days prior to the onset of symptoms; or

b) Any acute respiratory illness and having been in contact with a confirmed or probable COVID-19 case in the last 14 days prior to the onset of symptoms; or

c) Fever and ≥1 signs or symptoms of respiratory disease (eg, cough, dyspnea) who requires hospitalization and has no other etiology that fully explains the clinical presentation.

2) Confirmed case of COVID-19: A person with laboratory-confirmed infection with SARS-CoV-2, regardless of the presence of signs and symptoms.

3) Probable case of COVID-19: A person with inconclusive results of laboratory testing for infection with SARS-CoV-2.

Individual countries may need to adapt the case definitions based on their local epidemiologic situation.

Differential Diagnosis

1. Influenza.

2. Other viral respiratory infections.

3. Atypical pneumonia.

4. Pneumocystosis.

5. Other causes of ARDS

6. Middle East respiratory syndrome (MERS).

TREATMENT

Antiviral Treatment

As of March 21, 2020, there are no specific treatments of proven efficacy. The WHO recommends that potential treatments are used in the context of clinical trials.

Current suggestions from China are based on small-sample observational studies and include, for example, recommendations from the National Health Commission of the People’s Republic of China to use interferon alpha (5 million IU bid by inhalation) in combination with lopinavir/ritonavir (400 mg/100 mg bid orally; the first study of lopinavir/ritonavir is interpreted as not showing benefit, although it was too small to exclude relevant mortality benefit. Oseltamivir is also being considered.

Another suggestion, from the Department of Science and Technology of Guangdong Province and the Health Commission of Guangdong Province, is for chloroquine phosphate 500 mg every 12 hours for 10 days, irrespective of the severity of COVID-19, in patients without contraindications to this treatment. In those with severe gastrointestinal adverse effects the dosage may be reduced to 500 mg every 24 hours.

Clinical trials of other drugs are ongoing, including remdesivir for treatment of mild and severe COVID-19.

Based on early observations, use of systemic glucocorticoids in patients with ARDS may offer benefit.

Symptomatic Treatment

Treatment of COVID-19 is mainly supportive. In patients with features of respiratory failure and shock, oxygen therapy should be administered, with a target of SpO2 ≥90% (≥92%-95% in pregnant women). Start from an oxygen flow rate of 5 L/min and titrate as needed. Glucocorticoids are contraindicated, except for patients with absolute indications. Antibiotic treatment should not be used if bacterial superinfection is not suspected.

Management in sepsis and septic shock.

SPECIAL CONSIDERATIONS

Occupational Exposure of Health-Care Personnel

An exposure leading to infection refers to mucosal contamination with biological materials that may contain the virus. According to the US Centers for Disease Control and Prevention (CDC), materials that warrant postexposure management include respiratory secretions; there is no evidence indicating that other fluids (blood, urine, stool, and vomit) contain viable, infectious SARS-CoV-2. To assess the risk of transmission of SARS-CoV-2, consider:

1) Duration of exposure (longer exposure increases the risk of transmission).

2) Clinical symptoms of the patient.

3) Whether a facemask (and what type) was used by the health-care provider (HCP).

4) Whether the HCP used other personal protective equipment (PPE).

5) Whether aerosol-generating procedures were performed.

6) Whether a facemask was used by the patient.

High-risk exposures are defined as situations where an HCP is not wearing PPE that protects their mouth, nose, and eyes in the setting of droplets (eg, coughing) or during an aerosol-generating procedure, or situations where an HCP has direct contact with secretions from a patient with COVID-19 (cardiopulmonary resuscitation, intubation, extubation, bronchoscopy, nebulization, sputum induction).

Medium-risk exposures are defined as situations where an HCP has prolonged contact with a patient with COVID-19, which may result in mucosal or cutaneous exposure to potentially infectious materials.

Low-risk exposures are defined as situations where an HCP is using appropriate PPE but has prolonged close contact with patients with COVID-19. Although the currently available guidance on hygiene, sanitary standards, and use of PPE should be sufficient, it is nevertheless possible that due to oversight mistakes can be made, leading to SARS-CoV-2 transmission.

No occupational risk of exposure to SARS-CoV-2 is a risk category for HCPs who have no direct contact with COVID-19 patients, do not enter hospital wards or isolation wards for COVID-19 patients, and follow the routine safety precautions.

In case of exposure to biological materials from a patient with suspected SARS-CoV-2 infection, the exposed HCP should be treated as having high-risk or medium-risk exposure.

In the case of high-risk and medium-risk exposures, the HCP should undergo active monitoring and should be considered to be suspended from work for 14 days following the exposure. Active monitoring refers to monitoring performed by public health authority that regularly contacts the individuals potentially exposed to SARS-CoV-2 to assess them for the presence of symptoms. Communication may include telephone calls or internet-based means and should occur at least once a day. If an exposed HCP develops symptoms consistent with COVID-19, they should immediately self-isolate and notify public health authorities to arrange further evaluation (epidemiologic studies, need for hospitalization).

According to the European Centre for Disease Prevention and Control (ECDC), in the case of low-risk exposure, for 14 days after the exposure the HCP should perform self-monitoring with delegated supervision, which means the HCP performs self-monitoring with oversight by their health-care facility’s occupational health or infection control program or public health authorities. The exposed HCPs measure their temperature and assess themselves for other symptoms of respiratory tract infection. Temperature should be measured 2 times a day, including before starting work. HCPs who do not develop fever or other symptoms are not restricted from work. HCPs who develop symptoms consistent with COVID-19 should immediately self-isolate and notify public health authorities to arrange further evaluation.

HCPs who develop clinical symptoms consistent with COVID-19 must contact their point of contact (public health authorities or their health-care facility’s occupational health program) before returning to work, regardless of their risk exposure category.

PROGNOSIS

In the majority of cases COVID-19 has a mild course. In the elderly patients and those with chronic medical conditions the risk of acute respiratory failure and death is high.

PREVENTION

Specific Prevention

Vaccination: None available.

Nonspecific Prevention

1. General recommendations:

1) Frequently performing hand hygiene with soap and water or alcohol-based hand sanitizers.

2) Avoiding touching the face.

3) Reducing travel to a minimum.

4) Avoiding crowds and large gatherings.

5) Maintaining at least a 1-meter distance from others.

6) Avoiding contact with individuals with respiratory symptoms.

2. Quarantine or self-isolation: Healthy individuals who had contact with an infected person undergo a 14-day quarantine. The type of quarantine (self-observation, staying at home, quarantine in a hospital) depends on the type of contact (high-risk vs low-risk exposure) and is determined by local public health authorities.

3. Isolation of infected individuals: Isolation precautions can be used (1) to prevent droplet transmission or direct contact transmission or (2) during aerosol-generating procedures, to prevent airborne transmission. Before entering the patient room, don a set of PPE. After leaving the room, PPE should be removed in a designated area with a waste container for single-use PPE and hand decontamination equipment.

Precautions for droplet transmission and direct contact transmission: Patients should be placed in well-ventilated rooms with access to a washroom (in rooms with natural ventilation an average ventilation rate of 60 L/s per patient should be provided). If available, single-patient rooms are preferred. Patients with confirmed SARS-CoV-2 infection can be cohorted. Spacing between beds should be ≥1 meters. When possible, designated HCPs should be assigned to provide care for the patients. The number of visitors should be restricted. A log of all persons entering the room should be kept (including HCPs and visitors). Medical equipment should be single-use or dedicated for a single patient only (in the case of reusable equipment, eg, stethoscope, thermometer, blood pressure monitor, pulse oximeter). If reusable equipment is shared by different patients, it should be disinfected between uses. Room surfaces and equipment in the patient’s environment should be regularly cleaned and disinfected. Transport of patients within the hospital should be limited to a minimum. When feasible, portable diagnostic equipment should be used (eg, bedside radiograph). If the patient must be transported (eg, for diagnostic evaluation), use the shortest route and notify the HCPs in the receiving area in advance. The patient should be wearing a facemask. Transport personnel and receiving personnel having contact with the patient must use PPE. Minimize exposure for staff, other patients, and visitors during transport.

Precautions for airborne transmission (airborne infection isolation rooms [AIIRs]): If available, aerosol-generating medical procedures should be performed in well-ventilated rooms maintaining constant negative pressure, providing ≥12 air exchanges per hour, and with controlled direction of airflow (preferably) or in a naturally ventilated room with an average ventilation rate ≥160 L/s per patient.

4. PPE: A minimum set of PPE should include (recommendations in different jurisdictions differ and evolve):

1) PPE for respiratory protection: Single-use respirator masks of a filtering facepiece 2 (FFP2) or 3 (FFP3) standard or the North American counterpart, N95, must be worn during aerosol-generating procedures when providing care to a patient with SARS-CoV-2 infection. Currently the WHO and the Public Health Agency of Canada recommend surgical masks as sufficient while providing routine care and reserve respirator masks for aerosol-producing procedures. It should be noted, however, that surgical masks must be frequently replaced and that they do not provide protection against airborne transmission of microbes.

2) PPE for eye protection: Goggles or a face shield.

3) PPE for body protection: A long-sleeved gown or protective suit.

4) PPE for hand protection: Gloves.

Health-care facilities should have PPE in different sizes.

Video instructions on wearing and removing PPE:

1) For airborne precautions (aerosol-generating procedures), see a video from Sunnybrook Hospital, Toronto, Canada: https://youtu.be/syh5UnC6G2k.

2) For droplet precautions, see a video from St Joseph’s Healthcare, Hamilton, Canada: https://youtu.be/i_J2qtM1Aus.

The sequence of wearing (donning) PPE: Before donning PPE, disinfect hands. Then don the gown followed by the respirator mask. Make sure the respirator mask fits snugly to the face (in the case of FFP2 and FFP3 respirators all exhaled air should be filtered by the respirator; facial hair can interfere with the proper fit). Put on goggles or a face shield. The goggles should fit over the respirator mask. The last step is donning gloves, which should extend to cover the wrists and cuffs of the gown.

Removing (doffing) PPE (when using a gown for body protection; some details of the procedures differ between jurisdictions): This procedure requires particular caution, because the surface of PPE may be contaminated with infectious material. Incorrect or careless removal of PPE may result in accidental contamination followed by virus transmission. Single-use equipment should be discarded immediately after removal in an infectious waste container. Reusable equipment (eg, face shields or goggles) should be placed in a designated container and decontaminated before next use according to the manufacturer’s instructions. Start by disinfecting your hands. First remove the gloves in a way that minimizes hand contamination. Then disinfect the hands. You may consider donning a new pair of gloves (not done in Hamilton). With the new gloves on (if used), remove the gown. The back of the gown should be grabbed and pulled away from the body, keeping the contaminated front part inside the gown. Turn the sleeves inside out. (Avoid touching the contaminated front part of the gown.) Disinfect the hands again. Remove the goggles/face shield without touching their front part. You may disinfect the hands. Remove the respirator mask (grasp the straps and carefully remove the respirator without touching its outer surface). Disinfect the hands. Discard the gloves put on before removing the gown (if a second pair of gloves is used). Disinfect the hands again. Individual health-care facilities should adjust the procedures for donning and removing PPE based on the type of available equipment.

5. Individuals caring for infants: Infants cannot use respirator masks or facemasks and require special precautions to prevent viral transmission. Adults should use a respirator mask, perform hand hygiene before touching the infant, and regularly disinfect toys and other objects in the infant’s environment.

6. Reporting: Individuals traveling from countries where COVID-19 is present or who had contact with a patient infected with SARS-CoV-2 should notify public health authorities and discuss further management.