Hydroxychloroquine for COVID-19: more harm than good?

- Jennifer Middleton, MD, MPH

EDITOR'S NOTE: The study discussed in this post was retracted by the Lancet on June 5 at the request of three of the study authors because they could no longer vouch for the accuracy of the primary data sources. For further details, see Dr. Middleton's June 8 AFP Community Blog post.

Hydroxychloroquine and chloroquine, with or without a second-generation macrolide antibiotic, have been touted as possible treatments for COVID-19 since the early days of the pandemic. A few small, open-label studies showed promise, but much of the medical community, including the American College of Physicians, continued to advise caution. A much larger registry study, published last week, casts further doubt on that early optimism.

The study authors reviewed data from over 96,000 patients across 671 hospitals worldwide of patients who were admitted with a positive SARS-CoV-2 test and divided them into cohorts of those who received hydroxychloroquine or chloroquine, with or without a macrolide (most commonly azithromycin), and those who did not receive any of those medications (the control group). Included patients received one or more of these medications within 48 hours of admission, were not on mechanical ventilation when the regimen was started, and did not receive antiviral treatment with remdesivir:

These specific exclusion criteria were established to avoid enrolment [sic] of patients in whom the treatment might have started at non-uniform times during the course of their COVID-19 illness and to exclude individuals for whom the drug regimen might have been used during a critical phase of illness, which could skew the interpretation of the results. Thus, we defined four distinct treatment groups, in which all patients started therapy within 48 h of an established COVID-19 diagnosis: chloroquine alone, chloroquine with a macrolide, hydroxychloroquine alone, or hydroxychloroquine with a macrolide. All other included patients served as the control population.

All four of the medication groups had a higher in-hospital mortality than the control group (hydroxychloroquine hazard ratio [HR] 1.335 [95% confidence interval 1.223, 1.457],  hydroxychloroquine with a macrolide HR 1.447 [95% CI 1.36, 1.531], chloroquine HR 1.365 [95% CI 1.218, 1.531], and chloroquine with a macrolide HR 1.368 [95% CI 1.273, 1.469]). Additionally, all 4 medication groups had a higher risk of new onset ventricular arrhythmia (hydroxychloroquine HR 2.369 [95% CI 1.935, 2.900], hydroxychloroquine with a macrolide HR 5.106 [95% CI 4.106, 5.983], chloroquine HR 3.561 [95% CI 2.760, 4.596), and chloroquine with a macrolide HR 4.011 [95% CI 3.344, 4.812]). 

The study authors employed multiple techniques to control for potentially confounding variables, including baseline comorbid conditions, age, sex, ethnicity, and smoking status. The authors note that "[d]ue to the observational study design...a cause-and-effect relationship between drug therapy and survival should not be inferred" and that "[r]andomised clinical trials will be required before any conclusion can be reached regarding benefit or harm of these agents in COVID-19 patients."

We will have to wait for randomized controlled trials to definitively answer the question of causation, but for now, the best evidence to date suggests that they are unlikely to be helpful and may even worsen outcomes. Stockpiling them and/or taking them as a preventive measure (despite certain high-profile persons touting as such) is not recommended by the National Institutes for Health and may limit their access to the patients who truly can benefit from them (especially patients with lupus and other connective tissue diseases who rely on hydroxychloroquine).

AFP's comprehensive list of COVID-19 resources is being regularly updated if you'd like to read more about the latest findings related to the pandemic.

Multisystem inflammatory syndrome associated with COVID-19

- Kenny Lin, MD, MPH

One of the few comforting findings in the COVID-19 pandemic has been that most children older than one year of age have a less severe clinical course than adults. A large case series from China suggested that about half of infected children have mild symptoms (acute upper respiratory tract infection or gastrointestinal symptoms, including diarrhea) while only 1 in 20 develop hypoxia, respiratory failure, or other organ failure. In a U.S. case series, two-thirds of infants younger than 12 months were hospitalized; the corresponding figure in older children was 5 to 15 percent. As a pediatric infectious diseases specialist at New York University recently told a New York Times reporter, "The idea that children either don't get COVID-19 or have really mild disease is an oversimplification."

On April 7, Hospital Pediatrics published a case report of a 6 month-old infant who was hospitalized for classic Kawasaki disease and had a positive result on a reverse transcription polymerase chain reaction (RT-PCR) test for COVID-19. At that time, it was not clear if the COVID-19 diagnosis was coincidental or associated with this rare vascular inflammatory condition. On May 7, the Lancet published a report of a cluster of 8 cases of children with hyperinflammatory shock (atypical Kawasaki disease, Kawasaki disease shock syndrome, or toxic shock syndrome) who presented to a children's hospital in London during a 10-day period in the middle of April. Within one week, more than 20 children with similar clinical features were admitted to the pediatric intensive care unit (PICU), half of whom tested positive for SARS-CoV-2.

In Bergamo, Italy, the incidence of Kawasaki-like disease increased 30-fold between February and April at the height of the epidemic. Compared to a historical group of children with Kawasaki disease prior to the pandemic, these children were older and had a higher rate of cardiac complications. Investigators in France and Switzerland described a series of 35 children (31 of whom tested positive for SARS-CoV-2) who were treated in PICUs for acute heart failure due to a severe inflammatory state.

Last week, the U.S. Centers for Disease Control and Prevention (CDC) issued an official health advisory to provide information to clinicians about multisystem inflammatory system in children (MIS-C) associated with COVID-19. The case definition for MIS-C is as follows:

- An individual aged < 21 years presenting with fever, laboratory evidence of inflammation, and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological); AND

- No alternative plausible diagnoses; AND

- Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or COVID-19 exposure within the 4 weeks prior to the onset of symptoms.

Fortunately, standard treatment for Kawasaki disease (described in a 2015 article in AFP), including intravenous immunoglobulin, corticosteroids, and aspirin, thus far appears to be effective in treating MIS-C associated with COVID-19.

Can persons with type 2 diabetes safely fast during the month of Ramadan?

- Jennifer Middleton, MD, MPH

Many of those who celebrate the month of Ramadan, which began on April 23 this year, are unable to share this holiday's traditions with loved ones due to the COVID-19 pandemic. Although Muslims are unable to celebrate the iftar (the meal breaking the day's fast after sunset prayers) with those outside of their immediate family due to social distancing recommendations, the importance of fasting during the month of Ramadan has not changed. Fasting is expected of all adult Muslims from sunrise until sunset during the 30 days of Ramadan, excepting those who would endanger their health from doing so. Muslim persons with type 2 diabetes often still wish to fast despite the risks of hypo- and/or hyperglycemia, and a recent randomized controlled trial (RCT) from Singapore suggests those with decent baseline glycemic control can safely participate in fasting.

The RCT, published in the current issue of the Annals of Family Medicine with an accompanying editorial, studied FAST, a new clinical tool:

To address the need for a culturally tailored standard for diabetes care during the month of Ramadan, a multidisciplinary team of clinicians gathered to design an empowerment-based collaborative clinical tool called the Fasting Algorithm for Singaporeans with Type 2 Diabetes (FAST). It is a stepwise clinical decision-making tool with risk-assessment screening, Ramadan-specific patient education with self-monitoring of blood glucose (SMBG), structured glucose-lowering medication modification guidance for health care clinicians, and novel self-dose adjustment guidance based on SMBG readings during Ramadan.

The researchers randomized 97 patients with type 2 diabetes who planned to observe fasting during the month of Ramadan into an intervention group (using the FAST tool) or a placebo group (usual care). Participants were excluded if their baseline hemoglobin A1c was greater than 9.5%. Study groups were further stratified into patients using and not using insulin. Intervention group participants had improved fasting blood sugars (-3.6 mg/dL vs +20.9 mg/dL in the control group for a difference of 24.5 mg/dL [95% confidence interval 11.3-37.7]) with no statistically significant difference in postprandial blood sugars compared to participants in the control group. There were no major hypoglycemic events in either group. The intervention group had 1 verified minor hypoglycemic event and the control group had 5, though this difference was not statistically significant. Although the study authors lauded the improvements in the intervention group's blood sugars during the trial, more patient-oriented outcomes such as hypoglycemia were not significantly different (though it's possible that a better powered trial might have demonstrated a more robust difference). At the very least, though, the FAST tool appears to provide a culturally respectful approach to frame discussions with patients with type 2 diabetes planning to fast during the month of Ramadan.

The accompanying editorial considers whether the FAST trial's findings might also apply to other persons with type 2 diabetes who may be fasting, whether they are required to fast before a procedure or engaging in intermittent fasting with the goal of weight loss. With continued interest by many in intermittent fasting, keeping an open dialogue with our patients about safety and options is of critical importance. This 2015 AFP Curbside Consultation provides additional guidance for supporting patients with type 2 diabetes who choose to fast.

Maintaining connection to social traditions when possible, be they religious or otherwise, can support well-being and resilience during this challenging time. This AFP article on "The Spiritual Assessment" includes several tips for understanding our patients' faith traditions and supports, and the Ethnic Minorities subsection of the AFP By Topic: Care of Special Populations includes additional resources to increase our cultural competency and respect.

Medical student perspectives on COVID-19

- Enkhee Tuvshintogs, MD, AFP Resident Representative

For this post, I interviewed medical students in their second, third, and fourth years to share some of the ways that COVID-19 has impacted their education, training, and understanding of medicine going forward.

“When [we] hear ‘we need more doctors and providers!’ we want to [help] but we can’t right now. It is a weird thing,” says second-year student Alicia Hobbs (AH).

Medical students usually follow a strict timeline of classes, rotations, and examinations. Going through medical school is like “drinking from a fire hose.” It requires a constant balance of time, energy, learning, and growth. This path was altered by COVID-19.

AH had only been two weeks into her dedicated study time for the United States Medical Licensing Examination (USMLE) Step 1. Amidst her studying, she followed the news about the pandemic and grew more concerned as the situation evolved. Eventually the test that was scheduled for April got moved back to May. She is still not sure if it will happen. Her “clinical rotations have changed as well. [They] were supposed to start third year in the first week of May; that has been pushed back to mid-July now.”

Michelle Do (MD) explains that she had her fellow third year medical students are “kind of in between. We know some clinical duties; [each person’s] skill varies based on the rotations they did. ... Most medical students want to help - they care about the community.” Many are volunteering at drive-through screening sites, picking up groceries for people who can’t get them, providing child care, participating in “phone-a-senior” groups, and staying involved as much as they can. Still, the impact of COVID-19 is apparent. Their fourth year schedules - carefully planned with specialty-specific away rotations or sub-internships in other locations - are now up in the air. Their USMLE Step 2 examinations have been postponed, too.

Perhaps the most bittersweet changes have affected fourth year medical students. When most “stay-at-home” orders started, students all over the U.S. were waiting for the much anticipated Match letters that announced where they would be going for their residency. Not only was Match Day changed into a virtual experience, graduation ceremonies will be different as well. Many students like Libby Wetterer now have the interesting task of planning to move to another city or state from a distance. She has “begun to do purely virtual apartment searching” and has been also having “Zoom calls and group chats with her soon to be co-residents.”

MD, like many students, feels “conflicted - [she] wants a good educational experience, but [she] is also worried about being an asymptomatic carrier.” AH is thinking about the implications for COVID testing “knowing who’s immune and who’s not. [We are thinking about] how to look at a systems-approach for when something like this happens again. How to have better screening, stockpiles, PPE, etc.” The situation may put a different perspective on what scope of care they may select in the future. Students have begun to talk about the breadth of specialties - whether a particular specialty is so narrow that they can no longer do intubations, or if they would even want to do intubations in hazardous situations like this in the future.

Restrictions on participating in direct patient care recommended by the American Association of Medical Colleges were intended to safeguard their health, but medical students have been left feeling torn. They see their calling, but they also recognize the barriers. Rather than be disheartened, they are instead instinctively finding creative ways to support practicing health professionals and their communities.