Lindsay Cormier, PhD, MPH, Health Watch USA, Eastern Kentucky University, Lexington, Kentucky, USA


Lindsay Cormier, PhD, MPH

 protocols for access to President Joseph Biden, protocols which recently detected SARS-CoV-2 in a member of the Israeli delegation, the CDC appears to be on the verge of relaxing infection disease strategies. During the CDC’s June 2023 Healthcare Infection Control Practices Advisory Committee (HICPAC) meeting, concerns were expressed regarding proposed updates to existing infection control guidance for health care facilities which would place patients, health care workers, and nursing home residents at risk.



The new proposals elicited many comments from prominent public health organizations, patient and worker safety organizations, labor unions, and other experts (Table 1). The CDC was complimented for updating recommendations, and there was uniform agreement that switching to a paradigm of air and touch transmission pathways, as opposed to droplet and airborne, was needed.

However, many proposals raised concern. Like the flawed 

, CDC/HICPAC analyzed studies were plagued with poor adherence and design issues and ignored other applicable research. One commentator stated that one cannot ethically design an optimal masking trial. The 

. One should refrain from throwing out decades of occupational research in favor of a few poorly implemented randomized controlled trials.

HICPAC Commentators Included public (*) and HICPAC Liaison (**) commentators.

Videos of the CDC Presentation and Public Comments can be viewed at: 

(To view larger, right-click the image, and click "open image in new tab." The image will show in a new tab.) 

CDC/HICPAC is on the verge of adopting several problematic policies:
 
1. CDC/HICPAC proposes 3 levels of aerosol protection. Commentators disagreed with that approach because it maintains existing recommendations that reserve N95 respirators for only select pathogens (eg, measles, varicella) and “pandemic-phase” pathogens (eg, influenza, coronaviruses) and recommends a surgical mask for other respiratory viruses, including “seasonal” influenza and coronaviruses. Different tiers of protection between pandemic and seasonal phases for the same pathogens are arbitrary and ignore decades of research. Proposals also weaken protections for novel viruses. 

Negative pressure rooms were not recommended

 for MERS, SARS-CoV-1, SARS-CoV-2, or novel pathogens.

2. CDC/HICPAC proposes Enhanced Barrier Precautions (EBPs) for nursing homes where barrier precautions are only recommended for staff-patient interactions with high transmission risk. EBPs are 

,which found that some low-risk activities, such as passing meds, are performed so commonly that staff clothing contamination would occur. Additionally, residents under EBPs can still participate in normal facility activities. Disturbingly these recommendations are being advocated to control 

 and Carbapenem-resistant Enterobacteriaceae transmission.

3. Overall, there was a concern that the CDC/HICPAC continued to propagate watered-down crisis standards by proposing only a minimal standard for infection control programs. This crisis-standards approach during the COVID-19 pandemic led to extensive health care worker and patient infections, though tracking of both has been 

Additional areas for improvement include the omission of ventilation standards. Recommendations for more protective, reusable elastomeric respirators, powered air-purifying respirators (PAPRs), and preadmission testing and surveillance for infectious diseases are omitted. It is unclear how, if at all, safe staffing levels will be addressed.

CDC/HICPAC did not discuss updates for source control recommendations that would reflect the lessons learned from the COVID-19 pandemic. Source control is essential to prevent respiratory virus transmission, especially for viruses with significant presymptomatic transmission, such as 

. This is especially important for children and people with disabilities who cannot wear masks and immunocompromised individuals. Several commentators supported continued universal masking in health care facilities. The effectiveness of source control was illustrated by a 

which observed a 69% decrease in SARS-CoV-2 aerosols with the implementation of mask mandates. Since community SARS-CoV-2 infections are currently not collected, facility risk cannot be determined until delayed indicators of increased hospitalizations and deaths occur.

The CDC insufficiently tracks hospital-acquired respiratory infections. For example, CDC no longer requires data submission of hospital-acquired COVID-19 infections. Even when it did, a COVID-19 infection was 

 if it occurred in a currently hospitalized patient 14 or more days after admission. This metric captured only a small proportion of infections.

Finally, the process of recommendation formulation is flawed and lacks transparency. For example, important committee votes are held before and not after public comment. Meeting presentations are not publicly posted. Public comments from the meeting were recorded and published by an advocacy organization, not a governmental agency (Table 1).

HICPAC’s composition was a concern for many commentators. As stressed by M.K. Fletcher, MSPH, BS, the committee should include “aerosol scientists and ventilation experts, respirator protection experts, and industrial hygienists.”

The United States’ post-emergency infection control strategy involves scaling back data collection, weakening guidance, not effectively reporting health care worker or patient acquisitions, and not setting firm and effective standards for control. HICPAC/CDC is on the verge of weakening contact precautions (by adopting EBPs) and weakening airborne precautions, thereby ignoring decades of occupational health research. Lara Jirmanus, MD, MPH, from 

, stressed that without firm and effective standards, there would be limited accountability of facilities and that, if HICPAC proposals are adopted, we can expect lax infection control practices and higher rates of worker and patient infections.

We all should heed the wisdom of philosopher Lao Tzu: If one does not change direction, one may end up where one is heading.

Articles

In this opinion article, the authors discuss their concerns about the recent HICPAC/CDC proposals on infectious diseases. 

One Step Forward, 2 Back: CDC's Proposals for Infection Control in Health Care Facilities

The United States and much of the world were caught off guard by the rapid rise in RSV infections. In an almost knee-jerk explanation, many attributed this to the lack of respiratory syncytial virus (RSV) cases and immunological exposure during the preceding year. In a news release, the United States CDC even stated: “… we’re seeing more RSV because, in the past two years, we’ve not seen infections in children as we have. And so these children, if you will, need to become infected [with RSV] to move forward because it’s a disease prevalent in children.” In many circles, this was interpreted as masks, and avoiding crowded settings was harmful since it hurt natural immunity. The concept of “

Centers for Disease Control and Prevention

However, when this statement was made in early November 2022, the total number of RSV cases in the preceding year approximated those in the United States (See Figure IA), even though pediatric hospitals were 

. In addition, according to the National Center for Educational Statistics (NCES), there were few school closures in the United States during the 2021 to 2022 school year, with 

over 98% of school districts reporting in-person learning

, with the remainder reporting hybrid or remote.

Another plausible explanation was the “immune theft,” or immunodeficiency, caused by previous SARS-CoV-2 infection. As of February 2022, the United States CDC estimated that over 

 in the United States had been infected with SARS-CoV-2. Immunocompromise has been found with other viral infections such as measles which can cause decreased antibody function, and seasonal flu, which can cause lymphopenia.



Other countries have also had similar epidemiological experiences with RSV. 

 a prominent peak in RSV cases can be seen in the Fall of 2021 and Fall of 2022. If lack of exposure to RSV were a cause, one would not expect an even more significant number of cases in the 2022-23 RSV season (see Figure IB).



This RSV case pattern was also seen in Sweden

. As discussed in Bergmann S. and Lindström M.’s 2022 book 

 there was almost a total lack of public masking in Sweden, and nationwide closure of kindergartens and primary schools never occurred. Thus, there was little opportunity for “immune debt” to occur, yet RSV cases surged during the ensuing year of the pandemic (see Figure IC).

Figure IC: RSV cases per week Graph modified from 



Finally, in China, where there is very little available data, a huge RSV surge in hospital admissions was not seen 

at a pediatric hospital in Shanghai, China,

 when communities reopened in August 2020. China had one of the most stringent lockdowns, and the 2020 to 2021 RSV season and exposure to COVID-19 were limited, with relatively few cases. Despite the lack of exposure to RSV, a large was of RSV hospitalizations did not occur (Figure ID).

In a non-peer-reviewed preprint by Wang L et al children were reported to be almost twice as likely to develop an RSV infection if they had a prior documented COVID-19 infection. Other diseases, such as streptococcal tonsillitis, may also be impacted, which has been observed to have a 34% increase in post-COVID-19 patients. Thus, a post-COVID-19 immune deficiency might also explain the surge of scarlet fever observed in the United Kingdom.

Figure ID: From Frontiers in Microbiology, 

Children’s Hospital of Fudan University



Anthony Leonardi and Rui Proenca first described immunodysfunction and lymphopenia in an article published in Frontiers of Immunology.    

 later verified the finding and found that dysfunction may persist for 8 months (the longest time studied) in long COVID patients. This dysfunction was characterized as having “highly activated innate immune cells and a lack of naive T and B cells.” A recent report by Shen XR et al of utmost concern 

 T-Cells. They postulated a direct infection through an independent, non-ACE-2 receptor, which caused pronounced cellular apoptosis.

No one knows how severe or long-lasting post-COVID-19 immunodeficiency will be. Of concern is that reinfections can commonly occur in adults and maybe even more frequently in children. Laboratory evidence indicates that, unlike adults, immunologically SARS-CoV-2 

 “robust memory B cell responses.” Thus, reinfections can be expected to occur in children, possibly at a greater frequency than in adults, and carry a 

significant and additive risk of long COVID

, multisystem inflammatory syndrome, and immunosuppression.

These findings also support the contention that infections can cause stealth hospitalizations and deaths from COVID-19; and underscores the inappropriateness of protocols, such as those used by the 

, of only counting hospitalizations caused by COVID-19 in patients who have a positive test and receive corticosteroids. These protocols can underestimate COVID-19 hospitalizations by a factor of 3 and ignore the plethora of long COVID complications affecting many organ systems. After the acute phase of the infection, 

 the total number of COVID-19 deaths.

Most importantly, with little to no evidence, the attribution that masking and lack of exposure is the primary driver of the surge in bacterial and viral infections feeds into the narrative of anti-public health conspiracy theorists and discourages critical interventions from mitigating these infections.

Videos

Post-COVID-19 immune dysfunction is supported by epidemiological, clinical, and laboratory evidence. Attributing, with little to no evidence, that masking and lack of exposure is the primary driver of increases in bacterial and viral infections discourages critical interventions needed to stop the spread of disease.

Is the Rise in RSV Infections Associated With Immune Debt or SARS-CoV-2 Immune Dysfunction?

Many who are on ACE (angiotensin converting enzyme) Inhibitors and ARBs want to know what they should do in the midst of the COVID-19 pandemic. First and foremost, always consult a physician before making any decisions. The interaction between ACE Inhibitors and the COVID-19 virus has not been verified by clinical studies, but there is laboratory and animal evidence that raises concerns. Concerns which the NIH Director’s Blog further fueled by reiterating that the virus can adapt to bind to angiotensin converting enzymes (ACE2).

Concerns have also been raised regarding a number of studies which found that the COVID-19 co-morbidity with the highest incidence was hypertension.

The CDC does not list hypertension as a co-morbidity for the flu.

MD, the director of the US Centers for Disease Control and Prevention’s National Institute of Allergy and Infectious Diseases, recently reported to state the following: “wondered why someone with well-controlled hypertension would have a much greater chance of dying from COVID-19. He urged delving into this deeper and finding out which medications those individuals were taking,”

according to MedScape. He also stated, “If you look at the mechanistic rational for concern, it is there and it is firm.”

Authorities are split on what to do if a person is already on ACE Inhibitors and ARBs. Many in the United States have advocated to stay the course, until more information is known.

Switching medications may be difficult at best due to possible hypertensive rebound and exacerbation of high-blood pressure, especially in high risk patients.

A few authors feel these drugs may help COVID-19 patients.

However, some of the underlying Chinese laboratory research bolstering this contention may have methodological flaws

and one clinical trial regarding the provision of Recombinant Human Angiotensin-converting Enzyme 2 to COVID-19 patients has been withdrawn because of unfavorable results in a small pilot study.

Another research group out of England has recommended attempting to withdraw these medications if a COVID-19 infection develops in patients with mild diabetes or cardiovascular disease; and possibly those with mild disease and high risk of infection (such as healthcare workers).

Thus, to put it simply, if you are on an ACE Inhibitor at home during this COVID-19 epidemic and you do not have COVID-19, you have two choices:

1. You can stay at home performing reverse isolation and have little risk of contracting the virus. And come off your medications you may increase your risk of a stroke or heart attack.

2. You can stay at home performing reverse isolation and have little risk of contracting the virus. And stay on your medications without increasing your risk of a stroke or heart attack.

It seems in an environment of decreased medical access and monitoring due to COVID-19, the latter may well be the safest choice. 

However, patients should always consult their physician for recommendations regarding their care. Changing medication that treats high blood pressure or heart failure can be a complicated process and should never be attempted without professional guidance.

It is also important to weigh the risk and benefits depending on the prevalence of the COVID-19 virus in your area and your comorbidities for severe COVID-19 disease

Similar theoretical concerns exist for ibuprofen (Advil) and thiazolidinediones (a diabetic drug). There is less data regarding these drugs, since they are not designed to target the angiotensin pathways. 

At the least, until this controversy can be resolved, if you are on one of these medications one should perform strict social distancing, and reverse isolation and protect yourself from contracting COVID-19. Staying safe at home is best and follow strict recommendations when contacting the public. Providers should be cautious starting new patients on these medications, especially for mild conditions.

http://www.healthwatchusa.org/downloads/20200412-ACE-Inhibitor-COVID-19_Health_Watch_USA.pdf

1)  Collins, F.  Genomic Study Points to Natural Origin of COVID-19.  NIH Director’s Blog.  Mar. 26, 2020.   

https://directorsblog.nih.gov/2020/03/26/genomic-research-points-to-natural-origin-of-covid-19/


	  
	(2)  McMichael TM, et al., COVID-19 in a Long-Term Care Facility - King County, Washington, February 27–March 9, 2020.  MMWR.  March 18, 2020.  

https://assets.documentcloud.org/documents/6812675/CDC-Life-Care-Center-of-Kirkland.pdf


	  
	(3)  Sanchis-Gomar F, et al.  Angiotensin-Converting Enzyme 2 and Anti-Hypertensives (Angiotensin Receptor Blockers and Angiotensin Converting Enzyme Inhibitors) in Coronavirus Disease 2019 (COVID-19). Mayo Clinic Proceedings. March 30, 2020.   

https://els-jbs-prod-cdn.jbs.elsevierhealth.com/pb/assets/raw/Health%20Advance/journals/jmcp/jmcp_ft95_3_5-1585588116123.pdf


	  
	(4) Zhou, F, et al.,     Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.  The Lancet.  March 28, 2020.  

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30566-3/fulltext


	  
	(5)  Centers for Disease Control and Prevention.  People at High Risk For Flu Complications.  Updated August 27, 2018.   

https://www.cdc.gov/flu/highrisk/index.htm


	  
	(6)  Fryhofer SA.  Antihypertensive Drugs During COVID-19:  Still Up in the Air.   Medscape.  April 11, 2020.  

https://www.medscape.com/viewarticle/928099

(7)  COVID-19 Update with NIAID’s Anthony Fauci, MD; March 18, 2020.  JN (JAMA Network) Learning March 19, 2020.  

https://edhub.ama-assn.org/jn-learning/audio-player/18324686

  
	  
	(8)  Kuster GM, Pfister O, Burkard, T, et al.  SARS-CoV2: should inhibitors of the renin–angiotensin system be withdrawn in patients with COVID-19?  European Heart Journal.  2020.  0:1–3.  

https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehaa235/5810479


	    
	(9)   Vaduganathan M, et al.    NEJM. March 30, 2020.  DOI: 10.1056/NEJMsr2005760   Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19   

https://www.nejm.org/doi/full/10.1056/NEJMsr2005760?cid=DM89279_NEJM_COVID-19_Newsletter&bid=174664565


	     
	(10)   Phend C.  Don't Stop ACE, ARB Drugs Over COVID-19 Concern, Groups Urge - Clear potential for harm from withdrawal trumps questionable theoretical risk from continuing   Med Page Today.  April 6, 2020.  

https://www.medpagetoday.com/infectiousdisease/covid19/85817


	  
	(11)  Kavanagh KT, Calderon LE   Infection Control Today.  March 26, 2020 (updated March 31, 2020)  

https://www.infectioncontroltoday.com/covid-19/evidence-continues-link-ace-inhibitors-severe-covid-19-symptoms


	  
	(12)  Recombinant Human Angiotensin-converting Enzyme 2 (rhACE2) as a Treatment for Patients With COVID-19.   ClinicalTrials.gov Identifier: NCT04287686  

https://clinicaltrials.gov/ct2/show/NCT04287686


	  
	(13)   Aronson JK and Ferner RE.  ACE Inhibitors and Angiotensin Receptor Blockers (ARBVs) in COVID-19?  

https://www.cebm.net/covid-19/angiotensin-converting-enzyme-ace-inhibitors-and-angiotensin-receptor-blockers-in-covid-19/

If you are on one of these medications one should perform strict social distancing and protect yourself from contracting COVID-19.

Viewpoint: What To Do About ACE Inhibitors During COVID-19 Pandemic


	Why is hypertension appearing to be a primary driver of COVID-19?

The incidence of hypertension is noticeably high in patients with COVID-19 and the high degree of targeting of older individuals is very unusual. A recent study by the US Centers for Disease Control and Prevention regarding the Kirkland Nursing home observed: “The most common chronic underlying conditions among facility residents were hypertension (69.1%), cardiac disease (56.8%), renal disease (43.2%), diabetes (37.0%), obesity (33.3%), and pulmonary disease  (32.1%).”

Thus, hypertension may be a primary risk factor and driver of the severe symptoms of COVID-19. The ACE2 Receptor is used by the coronavirus (SARS-CoV-2) to enter cells. A protease, TMPRSS2, is also required to prime the virus for cellular entry. Data suggests that serum of patients which have recovered from infection blocks this entry mechanism.

In a recent blog, the director of the National Institutes of Health, Francis S. Collins, stated:“The genomic data of the new coronavirus responsible for COVID-19 show that its spike protein contains some unique adaptations. One of these adaptations provides special ability of this coronavirus to bind to a specific protein on human cells called angiotensin converting enzyme (ACE2).”

Other researchers have observed that lisinopril and losartan can increase (or upregulate) the ACE2 Receptor mRNA cellular expression by five and three-fold, respectively.

 This has given rise to concerns that these inhibitors may increase ACE2 Receptor cellular surface expression leading to exacerbated viral load in cells.

There has been at least 1 review article which discusses this concern which recommended staying the course with ACE inhibitor therapy of hypertension, since it has also been observed to be protective of pulmonary damage in mice.

 The authors also appear to have a large number of declared conflicts-of-Interest with the drug industry. The laboratory research in mice used losartan (angiotensin II receptor antagonist) with an acute exposure not specified, and may not be adequate time for upregulation of ACE-2 receptor.

 In a prior publication, only a 30 minute pre-treatment of the inhibitor was used and the effect on ACE-2 receptor expression is unknown and therefore long-term viral effect on the lung cannot be determined.

There is mounting consensus that ACE inhibitors may be a primary driver of the severe symptoms. The concerns have been raised in the Lancet8 and most recently in Medscape.

If this is all true, then we may have identified how to mitigate the major pathology in COVID-19 and (similar to Tamiflu) have a mechanism of researching an exciting new therapy for this disease. Already, there is current research on Recombinant Human Angiotensin-converting Enzyme 2  at Clinicaltrials.gov #NCT04287686 and a blocker of TMPRSS2, camostat mesylate, has been approved for human use in Japan for another indication.

(Acknowledgement: Lindsay E. Calderon, PhD, MPH, Eastern Kentucky University, was a co-author on this update and responsible for research analysis.)

(1)    https://assets.documentcloud.org/documents/6812675/CDC-Life-Care-Center-of-Kirkland.pdf
	(2)    Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor.  Cel.  Mar. 4, 2020 [Online ahead of print]   https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(20)30229-4
	(3)    Collins, F.  Genomic Study Points to Natural Origin of COVID-19.  NIH Director’s Blog.  Mar. 26, 2020.  https://directorsblog.nih.gov/2020/03/26/genomic-research-points-to-natural-origin-of-covid-19/
	(4)    Re: Preventing a covid-19 pandemic: ACE inhibitors as a potential risk factor for fatal Covid-19.  BMJ.   Feb. 28, 2020.  Vol. 368.  https://www.bmj.com/content/368/bmj.m810/rr-2
	(5)    Kuster GM, Pfister O, Burkard, T, et al.  SARS-CoV2: should inhibitors of the renin–angiotensin systembe withdrawn in patients with COVID-19?  European Heart Journal.  2020.  0:1–3.  https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehaa235/5810479
	(6)    Kuba K., Imai Y, Rao S. et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury.  Nature Medicine. Aug. 2005.  11(8):875-879.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7095783/pdf/41591_2005_Article_BFnm1267.pdf
	(7)    Imai Y, Kuba K, Rao S, et al.  Angiotensin-converting enzyme 2 protects from severe acute lung failure.  Nature. July 7, 2005.  436:112-116.   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094998/
	(8)    Fang L, Karakiulakis G, Roth M.  Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?  The Lancet Respiratory Medicine.  March 11, 2020.   https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30116-8/fulltext
	(9)    Hughes S.  COVID-19 and Angiotensin Drugs: Help or Harm?.  Medscape.   March 25, 2020.  https://www.medscape.com/viewarticle/927542

ACE inhibitors up regulate (increase) the ACE2 receptor. This is the receptor the COVID-19 virus uses to attack the lungs.

Lindsay Cormier, PhD, MPH

Articles

One Step Forward, 2 Back: CDC's Proposals for Infection Control in Health Care Facilities

Is the Rise in RSV Infections Associated With Immune Debt or SARS-CoV-2 Immune Dysfunction?

Viewpoint: What To Do About ACE Inhibitors During COVID-19 Pandemic

Evidence Continues to Link ACE Inhibitors to Severe COVID-19 Symptoms