medRxiv preprint doi: https://doi.org/10.1101/2020.05.18.20066902; this version posted May 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .
Doxycycline and Hydroxychloroquine as Treatment for High-Risk COVID-19 Patients: Experience
from Case Series of 54 Patients in Long-Term Care Facilities
Imtiaz Ahmad, MD, MPH, FCCP1
Mohammud Alam, MD2
Ryan Saadi, MD, MPH3,6
Saborny Mahmud4
Emily Saadi, BS5
1Allergy, Sleep & Lung Care, 21st Century Oncology, Fort Myers, FL
2Infectious Disease Specialist, Cordial Medical PC, Farmingdale, NY
3Center for Market Access and Medical Innovation, Warren, NJ
4 Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
5 Yale University, School of Public Health, New Haven, CT
6Quantaira Health, New York, NY
Corresponding author : Imtiaz Ahmad, MD, Allergy, Sleep & Lung Care, 21st Century Oncology, Fort
Myers, FL. email : [email protected]
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.05.18.20066902; this version posted May 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .
Abstract:
Importance: Patients in long-term care facilities (LTCF) are at a high-risk of contracting COVID-19 due
to advanced age and multiple comorbidities. Without effective treatments, outbreaks in such facilities will
become commonplace and will result in severe morbidity and mortality. The effectiveness of doxycycline
(DOXY) and hydroxychloroquine (HCQ) combination therapy in high risk COVID-19 patients in long-
term care facilities is not yet understood.
Objective: The goal of this analysis is to describe outcomes after use of DOXY-HCQ combination in
high-risk COVID-19 patients in LTCF.
Design: Case-series analysis.
Setting: Three (3) LTCFs in New York.
Participants: From March 19 to March 30, 2020, fifty-four (54) patients, residents of three (3) LTCFs in
New York and diagnosed (confirmed or presumed) with COVID-19, were included in this analysis.
Exposure: All patients who were diagnosed (confirmed or presumed) with COVID-19 received DOXY-
HCQ combination therapy along with standard of care.
Main Outcomes and Measures: Patients characteristics, clinical recovery, radiological improvements,
medication side-effects, hospital transfer, and death were assessed as outcome measures.
Results: A series of fifty-four (54) high-risk patients, who developed a sudden onset of fever, cough, and
shortness of breath (SOB) and were diagnosed or presumed to have COVID-19, were started with a
combination of DOXY-HCQ and 85% (n=46) patients showed clinical recovery defined as: resolution of medRxiv preprint doi: https://doi.org/10.1101/2020.05.18.20066902; this version posted May 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .
fever and SOB, or a return to baseline setting if patients are ventilator-dependent. A total of 11% (n=6)
patients were transferred to acute care hospitals due to clinical deterioration and 6% (n=3) patients died in
the facilities. Naive Indirect Comparison suggests these data were significantly better outcomes than the
data reported in MMWR (reported on March 26, 2020) from a long-term care facility in King County,
Washington where 57% patients were hospitalized, and 22% patients died.
Conclusion: The clinical experience of this case series indicates DOXY-HCQ treatment in high-risk
COVID-19 patients is associated with a reduction in clinical recovery, decreased transfer to hospital and
decreased mortality were observed after treatment with DOXY-HCQ.
medRxiv preprint doi: https://doi.org/10.1101/2020.05.18.20066902; this version posted May 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .
Introduction:
The COVID-19 pandemic is straining the U.S. healthcare system due to increased hospitalization, ICU
admissions, and mortality. As of May 18, 2020, a total of 351,371 patients and 1,508,308 patients were
afflicted with COVID-19 in New York state and the United States, respectively1. In addition, 75,870
patients were hospitalized, and 28,339 patients died in New York alone1. Thus, New York has become the
epicenter of the world for the COVID-19 pandemic at the time of this publication2.
The COVID-19 virus affects the upper and lower respiratory tract, leading to acute respiratory failure.
Consequently, pro-inflammatory cytokines are released such as tumor necrosis factor (TNF), interferon-
alpha (IFNa), IL-1β, and IL-6, all of which are mediators of lung inflammation and fever3. Therefore,
symptoms of a COVID-19 infection include fever, cough, and shortness of breath (SOB). In addition, the
virus is associated with acute cardiac injury in 19.7% of hospitalized patients, manifesting as an ejection
fraction decline and an elevation in troponin I levels4.
Recent small studies in France and China demonstrated the limited efficacy of hydroxychloroquine
(HCQ) alone or in combination with azithromycin (AZ)5,6,7. However, concerns have been raised about
the use of the AZ-HCQ combination due to higher arrhythmogenic potential in high-risk patients with
pre-existing cardiac comorbidities and/or acute cardiac injury due to COVID-19. According to the Food
and Drug Administration (FDA) labeling, side-effects of AZ include “prolonged cardiac repolarization
and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes”8.
Additionally, QTc prolongation was found in a dose-dependent manner when chloroquine, an HCQ
analogue, was used alone or in combination with AZ8.
Doxycycline (DOXY) is considered to be an anti-inflammatory, immunomodulatory, and cardioprotective
drug 19. Both in-vitro and in-vivo studies demonstrated that doxycycline directly modulates the expression medRxiv preprint doi: https://doi.org/10.1101/2020.05.18.20066902; this version posted May 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .
of inflammatory mediators involved in COVID-19 pathophysiology (IL-8, IL-1β9, TNF10, MMP11, and
IL-612). In addition, Kalish et al showed a novel immunosuppressive mechanism for minocycline (a
DOXY analogue), as well as its possible additive anti-inflammatory effect when combined with
chloroquine or HCQ20. No cardiac side-effects are noted per the FDA labeling of DOXY13. In addition,
during reperfusion after myocardial injury, an acute release of matrix metalloproteinases-2 (MMP-2) is
noted14, and MMP inhibition after myocardial infarction yields preservation of left ventricular function15.
DOXY reduces the adverse LV remodeling in patients with acute ST-segment elevation myocardial
infarct (STEMI) and LV dysfunction, possibly via MMP inhibition pathway16. These potential
cardioprotective effects may have an additional implication in the COVID-19 patients with acute
myocardial injury.
Due to these scientific findings, we have undertaken a thorough review of this case series of high-risk
COVID-19 patients in nursing homes, who were treated with a combination of DOXY-HCQ.
Methods:
From March 19 to March 30, 2020, we analyzed the clinical outcomes of fifty-four (54) high-risk patients
who developed a sudden onset of fever, cough, and SOB, were diagnosed or presumed to have COVID-
19, and were treated with DOXY (100 mg PO BID for 7 days) and HCQ (two regimens: i) 200 mg PO
TID for 7 days or ii) 400 mg PO BID one day, then 400 mg daily for 6 days). The patients were residents
of three (3) long term care facilities (LTCF) in New York. Patients’ characteristics, clinical recovery,
radiological improvements, medication side-effects, hospital transfer, and death were assessed as outcome
measures in this population. Consent was obtained from all patients and/or families before starting
Doxycycline and Hydroxychloroquine to treat presumed and confirmed COVID-19 infection and
approved by the oversight medical boards. The retrospective review was approved by Corporate Clinical
Services. medRxiv preprint doi: https://doi.org/10.1101/2020.05.18.20066902; this version posted May 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .
High-risk patients were defined as patients who had at least one comorbidity, such as hypertension,
diabetes, coronary artery disease (CAD), congestive heart failure (CHF), chronic obstructive pulmonary
disorder (COPD), and cerebrovascular accident (CVA). Clinical recovery was defined as a resolution of
fever and SOB, or a return to baseline settings for ventilator-dependent patients. A return to baseline
ventilator settings was defined as a return of oxygen saturation and mode of ventilator to a baseline level.
Chest X-rays were ordered at the onset of symptoms. Follow-up chest r-rays were ordered if clinically
indicated.
Results:
In this series of fifty-four (54) patients, the median age was 67 yrs. (range 22-97 yrs.). Table 1
summarizes the characteristics and outcomes of all COVID-19 patients treated with DOXY-HCQ
combination in LTCFs in New York. 96% (n=52) tested positive for COVID-19 and 4% (n=2) were
presumed to have the viral infection due to clinical features. 85% (n=46) of patients showed clinical
recovery, defined by resolution of fever and SOB, or a return to baseline ventilator setting. 6% (n=3) of
patients died and 11% (n=6) of patients were transferred to acute care hospitals due to clinical
deterioration.
All patients became and remained afebrile within 0-5 days and SOB resolved or returned to baseline with
0-6 days of DOXY-HCQ initiation. 11% of patients (n=6) showed an improvement in chest X-rays. 30%
of patients (n=16) did not show chest X-ray improvement. 93% (n=50) did not display any side-effects of
DOXY-HCQ. 2% (n=1) had a seizure and HCQ was immediately terminated.
medRxiv preprint doi: https://doi.org/10.1101/2020.05.18.20066902; this version posted May 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .
There were 9 patients who did not complete the 7-day course of DOXY-HCQ due to hospital transfers,
death, or side-effects (Table 2). Excluding these patients, a total of 45 patients completed the DOXY-
HCQ combination therapy; all 45 patients clinically recovered (Table 3).
Discussion:
The COVID-19 pandemic created a huge burden on the U.S. healthcare system and increased the risk of
hospitalization, ICU admissions, and mortality. Recently, various drugs have been experimentally used,
and the most promising therapy involves HCQ and/or AZ. However, safety concerns are raised due to the
potential side-effects profile of both drugs, particularly when used in combination.
A recent open-label French study of only six (6) patients in hospital settings showed limited effectiveness
(no clinical outcomes reported) of combination of AZ-HCQ in treatment of COVID-19 patients, within
six days of treatment8. Subsequently, Raoult et al17 published another case series of 80 patients in hospital
settings with AZ-HCQ combination therapy and all but two patients showed clinical improvement.
However, 94% of patients were low-severity patients as evidenced by low (0-4) national early warning
score (NEWS). The impact of such combination therapy in a high-risk population like ours is unknown.
Another recently published Chinese randomized clinical trial conducted in a hospital setting among 62
patients treated with HCQ for 5 days showed improvement of pneumonia in the HCQ treatment group
(80.6%, n=25 of 31 patients) compared with the control group (54.8%, n=17 of 31 patients)6. 2 patients
showed mild adverse events including rash and headache. Detailed demographics of the patient
population were not published, however the mean (SD) age was 44.7 (15.3) yrs., much younger than our
patients. Compared to this study, our case series patients were much older and had significant multiple
comorbidities.
medRxiv preprint doi: https://doi.org/10.1101/2020.05.18.20066902; this version posted May 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .
So far, no study was published from the United States using HCQ alone or in combination with AZ or
DOXY. As a matter of fact, this study is the first case series conducted globally using a combination of
DOXY-HCQ in COVID-19 patients in nursing home settings. We treated our moderate to severe patients
in out-of-hospital settings and prevented hospital transfer in the majority of patients. Naive Indirect
Comparison showed a better outcome than the data reported in MMWR (reported on March 26, 2020)17
from a long-term care facility in King County, Washington where 57% of patients were hospitalized and
22% patients died. This effect can possibly be explained by the anti-inflammatory mechanism of action of
DOXY-HCQ.
However, data from the LTCF from King County, Washington was found to be similar to our population.
These data also showed a reduction of hospitalization by 44% among LTCF residents compared to
previously reported data by similar populations in MMWR.
A limitation of our case-series analysis is that there was no control population available.
Conclusion:
DOXY and HCQ combination therapy is known to be anti-inflammatory, and immunomodulatory in both
in-vitro and in-vivo studies. In addition, HCQ has anti-viral properties. Although this sample size is small
(n=54), the results suggest that early intervention of DOXY-HCQ may improve the clinical outcome of
high-risk COVID-19 patients suffering from moderate-severe symptoms in LTCF. These data is also
associated with a reduction of hospitalization by 44% among moderate to high severity COVID-19 LTCF
residents compared with previously reported data by similar populations from King county,
Washington18.
Given the massive pandemic created by COVID-19 virus, there is an emergent therapeutic need to
manage this disease with effective and safe drugs in an out-of-hospital setting for high-risk patients to medRxiv preprint doi: https://doi.org/10.1101/2020.05.18.20066902; this version posted May 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .
reduce hospitalization and ICU admission and manage acute ventilator shortage. A well-designed clinical
study is urgently needed to identify the appropriate patient population, optimize dosing regimen, and
assess side-effects of DOXY-HCQ combination therapy.
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medRxiv preprint doi: https://doi.org/10.1101/2020.05.18.20066902; this version posted May 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .
TABLE 1: Characteristics and Outcome of COVID-19 Patients Treated with DOXY-HCQ Combination in Three (3) Long Term Care Facilities
Characteristics LTCF Resident (n=54) % Reference Population (LTACH,WA)
Median Age, yrs. (range) 67 (22-97)
Sex
Male 33 61%
Female 21 39%
Comorbidities
Hypertension 49 91%
Diabetes 21 39%
CAD 31 57%
CHF 11 20%
CVA 20 37%
COPD 21 39%
Vent dependent*** 17 31%
Test Status
COVID-19 Positive 52 96%
COVID-19 Presumed 2 4%
Outcome
Clinically recovered** 46 85%
Transferred to hospital 6 11% 57%
Death 3 6% 22%
Radiology Abnormal CXR c/w Pneumonia 36 67%
Chest x-ray improved 6 11% medRxiv preprint doi: https://doi.org/10.1101/2020.05.18.20066902; this version posted May 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .
Chest x-ray not improved (possible lag time) 16 30%
Unavailable* 32 59%
Medication side-effect
Seizure 1 2%
None 50 93%
Unknown**** 3 6%
* Chest x-ray either not ordered, or not required or pending
** Recovery defined by resolution of fever and shortness of breath, or return to baseline vent setting
*** 65% (n =11) patients recovered and vent setting is returned to baseline
**** Not available as patients were transferred to hospital ! Dropouts means patients who did not complete a full course of DOXY-HCQ therapy due to transfer to hospital, death or side-effects. medRxiv preprint doi: https://doi.org/10.1101/2020.05.18.20066902; this version posted May 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .
TABLE 2: Characteristics COVID-19 Patients Who Did Not Complete DOXY-HCQ Combination Therapy in Three (3) Long Term Care Facilities Transferred Death Details to hospital Transferred to hospital with septic shock, patient 1 Yes No returned to nursing facility Transferred to hospital with septic shock, patient 2 Yes No returned to nursing facility
3 Yes Unknown* Transferred to hospital with respiratory failure HCQ discontinued due to seizure, patient continued with 4 No No DOXY. Stable
5 No Yes Died due to respiratory failure at nursing home Patient coded, was resuscitated and transferred to 6 Yes Unknown* hospital Transferred to hospital with respiratory failure and later 7 Yes Yes died in hospital Transferred to hospital with respiratory failure, patient is 8 Yes No in ICU
9 No Yes Died due to septic shock in nursing home
*Status unavailable at the time of reportin medRxiv preprint doi: https://doi.org/10.1101/2020.05.18.20066902; this version posted May 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .
TABLE 3: Outcome of COVID-19 Patients Treated with Complete 7 Days Course DOXY-HCQ Combination in Three (3) Long Term Care Facilities*
Characteristics LTCF Resident % Reference (n=45) Population (LTCF,WA)
Median Age, yrs. (range) 68 (22-97) Chronic underlying conditions
Hypertension 41 91%
Diabetes 18 40%
CAD 26 58%
CHF 8 18%
CVA 17 38%
COPD 17 38%
Vent dependent 12 27%
Outcome 0%
Clinically recovered** 45 100%
Transferred to hospital 0 0% 57%
Death 0 0% 22%
Radiology 0% Abnormal CXR c/w Pneumonia 28 62%
Chest x-ray improved 5 11% Chest x-ray not improved (possible lag time) 10 22%
Unavailable*** 30 67%
Medication side-effect 0%
None 45 100%
* This table includes all patients who completed a full course (7 day) of DOXY-HCQ therapy and excludes any patients who were transferred to hospital, death or developed side-effects due to DOXY- HCQ and did not complete the 7-day course.
** Recovery defined by resolution of fever, shortness of breath or return to baseline vent setting medRxiv preprint doi: https://doi.org/10.1101/2020.05.18.20066902; this version posted May 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .
*** Chest x-ray either not ordered, or not required or pending