It depends on the type of medication. The evidence from a few preliminary studies is complex. H-2 blockers might possibly decrease risk. H-1 blockers might possibly help reduce risk when paired with an H-2 blocker. One study found that Proton Pump Inhibitors (PPIs) may increase risk of infection with Covid-19. However, another smaller study found that a particular PPI might decrease risk of infection with Covid-19.

This article reviews the evidence.

The three types of medications discussed in this article are:
1. Histamine-1 Blockers
2. Histamine-2 Blockers
3. Proton Pump Inhibitors

“H1 antagonists, also called H1 blockers, are a class of medications that block the action of histamine at the H1 receptor, helping to relieve allergic reactions.” []

Examples of H-1 Blockers: Cetirizine (Zyrtec®), Loratadine (Claritin®), and Acrivastine, a.k.a. Benadryl Allergy Relief® (UK), Semprex (US). These are allergy medications.

“H2 antagonists … also called H2 blockers, are a class of medications that block the action of histamine at the histamine H2 receptors of the parietal cells in the stomach. This decreases the production of stomach acid.” Wikipedia

Examples of H-2 Blockers: Ranitidine and Famotidine (Pepcid®) are the two best known.

So the H-1 blockers are for allergies, but the H-2 blockers are for stomach acid. Then the proton pump inhibitors (PPIs) are for stomach acid as well.

“Proton-pump inhibitors (PPIs) are members of a class of medications whose main action is a profound and prolonged reduction of stomach acid production.” [Wikipedia]

PPIs are commonly used for indigestion and excess stomach acid. Examples include: Prilosec® (generic: Omeprazole), and Prevacid® (generic: Lansoprazole). Recent studies have found that these medications may help or may harm people, with regard to Covid-19.

1. Freedberg

A study published in Gastroenterology, by Freedberg et al., found that famotidine use was correlated with better outcomes for hospitalized Covid-19 patients [1]. As a result of this study, the MATH+ Protocol was amended to add famotidine as a prophylaxis for persons who are well and as a treatment for persons with mild Covid-19 who are quarantining at home.

The Freedberg study examined 340 hospitalized Covid-19 patients, 84 of whom used famotidine. They found a surprising benefit from that over-the-counter drug:

“Use of famotidine was associated with reduced risk for death or intubation (adjusted hazard ratio (aHR) 0.42, 95% CI 0.21-0.85) and also with reduced risk for death alone (aHR 0.30, 95% CI 0.11-0.80).” [1]

Patients taking famotidine were 58% less likely to either die or need intubation (ventilation), and overall they were 70% less likely to die. And that is an adjusted odds ratio, meaning that various confounding factors were statistically accounted for, to remove their influence on the values.

Think about that for a moment — 70% less likely to die. It’s an over-the-counter medication. Now this was a correlation, not a causation. You could always propose that the benefit was due to some other factor. Might it be the case that persons with excess stomach acid are, in general, less likely to die from Covid-19? But, no, that possibility was removed by this same study: “Proton pump inhibitors, which also suppress gastric acid, were not associated with reduced risk for death or intubation.” [1] So it’s not the fact that the person had excess stomach acid, nor is it merely that the stomach acid problem was corrected by the medication. Even so, this is one study and a correlation. We cannot be certain that taking famotidine will provide that benefit.

On the other hand, it’s a low-risk OTC medication that might have a substantial benefit. We always say, correctly, that studies like this find correlation, not causation. But in truth they are aimed at finding causation. The adjusted odds ratio means that one or more confounding factors were removed by means of statistics. And with more studies comes a greater likelihood that the correlation is also a causation. Studies like this one are “correlation in search of causation.”

2. Janowitz

In a case series, published in the journal Gut (2020), famotidine at high dosage was well-tolerated and was associated with improved symptoms for non-hospitalized patients [2]. Now a case series is less weighty, in terms of the evidence presented, than a cohort or case-control study or an RCT. But every bit of information helps. The fight against Covid-19 is a war, and in war, you use every weapon you have. A rifle is much more useful to a soldier than a knife, but we arm our troops with both.

“Results Ten consecutive patients with COVID-19 who self-administered high-dose oral famotidine were identified. The most frequently used famotidine regimen was 80 mg three times daily (n=6) for a median of 11 days (range: 5–21 days). Famotidine was well tolerated. All patients reported marked improvements of disease related symptoms after starting famotidine. The combined symptom score improved significantly within 24 hours of starting famotidine and peripheral oxygen saturation (n=2) and device recorded activity (n=1) increased. [2]

“Conclusions The results of this case series suggest that high-dose oral famotidine is well tolerated and associated with improved patient-reported outcomes in non-hospitalised patients with COVID-19.” [2]

In the Freedberg study, almost all the doses were less than or equal to 40 mg famotidine per day. In the Janowitz study, the doses were much higher, at 80 mg times three per day, which is 240 mg/day — higher than any single patient in the Freedberg study. However, good results were obtained in the Janowitz patients at that high dose. Since the Freedberg study carries more weight, and had a strong outcome of reducing case fatality by 70%, that dose range seems preferable.

3. Hogan

A preprint study published at medRxiv, by Hogan, Reed B., et al. found that a “Dual-Histamine Blockade with Cetirizine-Famotidine Reduces Pulmonary Symptoms in COVID-19 Patients.” [3]

Intervention: “110 high-acuity patients that were treated with cetirizine 10 mg and famotidine 20 mg b.i.d. plus standard-of-care.” [3]

The study used a combination of Histamine-1 (cetirizine) and Histamine-2 (famotidine) receptor antagonists to treat Covid-19. Rates of intubation and mortality were low. The dosage of famotidine used in this study were similar to Freedberg and lower than Janowitz. The dosage of cetirizine is the usual OTC dose of 10 mg.

Results: “the combination drug treatment resulted in a 16.4% rate of intubation, a 7.3% rate of intubation after a minimum of 48 hours of treatment, a 15.5% rate of inpatient mortality, and 11.0 days duration of hospitalization.” [3]

The weakness of this study is they had no controls, other than an informal comparison with published reports of COVID-19 patients. The rate of inpatient mortality at 15.5% has no point of comparison. The reduction in rate of intubation after 48 hours treatment is the most noteworthy outcome. A reduction from 16.4% to 7.3% after 48 hours makes the drug treatment seem effective. But again there is no point of comparison.

For this article, another study was used as a point of comparison [7]. That study of 7,995 patients across the 5-hospital Yale New Haven Health system had a 13.5% rate of mortality for hospitalized patients, and an 11.8% rate for invasive mechanical ventilation. In comparison, the use of both H-1 and H-2 blockers had a higher rate of mortality, but a lower rate of intubation.

Famotidine by itself (Freedberg) provided a substantial benefit. The addition of cetirizine in this study (Hogan) may or may not provide an additional benefit. There’s not enough evidence yet to show that adding an H-1 blocker to the famotidine, and H-2 blocker, will make the drug more effective.

4. Almario

This study, published in the American Journal of Gastroenterology, is titled: “Increased Risk of COVID-19 Among Users of Proton Pump Inhibitors” [5]. The study concluded that taking proton pump inhibitors, but not H2 blockers, increased risk of infection with Covid-19 by 2.15 times for once daily use, and by 3.67 times for twice daily use [5].

The overall cohort was 53,130 persons, of whom 3,386 were positive for Covid-19. The goal of the study was to compare the likelihood of infection with SARS-CoV-2 to the use of medications for stomach acid. Once daily use of any proton pump inhibitor (PPI) was associated with 115% increase (2.15 times), and twice daily use with a 267% increase (3.67 times), in likelihood of infection with Covid-19. The results were highly statistically significant (p less than 0.001) [5].

In this same study, the use of H-2 blocker medications for stomach acid, such as famotidine, once daily, provided a decrease in likelihood of infection by 15% (p=0.032). Twice daily use of H-2 blockers did not provide a statistically significant result. The result was statistically significant, but not highly so.

The idea is that PPIs decrease stomach acid, and stomach acid has a protective role. High acidity might destroy the SARS-CoV-2 virus, and low acidity might not. So it is possible that PPIs increase risk in this way, by removing a protective role for stomach acidity. But another possibility is that the medications have some type of effect on cells, which make it more difficult for SARS-CoV-2 to infect the cells themselves.

Famotidine and ranitidine (and others) are H2 blockers (also called H2 antagonists). So this study agrees with Freedberg and Janowitz that H2 blockers may help prevent Covid-19.

The next study, though, presents us with a problem. While Almario et al. found that PPIs increase risk of infection with Covid-19, Blanc et al. found that PPIs decrease risk by about the same amount:

5. Blanc

This study of 179 elderly patients, compared a group who tested positive to a group who tested negative for Covid-19 (rt-PCR test) [4]. The study considered whether any of the medications they were taking might have influenced their risk of infection.

Results: “Patients on PPIs were 2.3 times less likely (odds 25 ratio [OR] = 0.4381, 95% confidence interval [CI] [0.2331, 0.8175], P=.0053) to develop COVID-19 26 infection, compared to those not on PPIs.” [4]

Conclusion: “PPIs treatment lowered the risk of development of COVID-19 infection, and 30 antipsychotics and OADs [oral antidiabetics] decreased the risk of mortality in geriatric patients.”

Now there are differences between the two studies, Almario and Blanc. The latter group was elderly patients, and the former were from the general population, with a wider age range. Also, the Blanc study had only 63 patients on PPIs [4], while the Almario study had over 2600 persons on PPIs [5]. The smaller study size might be a factor. But when we look at the details of the Blanc data, it seems that the type of PPI makes a big difference.

“The types of PPIs taken by the COVID-neg patients were as follows: pantoprazole (N=16), lansoprazole (N=11), esomeprazole (N=8), omeprazole (N=4), and rabeprazole (N=1). PPIs taken by the COVID-pos patients were as follows: pantoprazole (N=15), esomeprazole (N=6), lansoprazole (N=1), and omeprazole (N=1)” [4].

Notice that pantoprazole had almost the same number in each group, 16 negative and 15 positive. That can’t be statistically significant. Lansoprazole had 11 negative and 1 positive. So it looks like lansoprazole users were much more likely to test negative. Esomeprazole was 8 versus 6 (neg v pos). That is probably a statistical wash. Omeprazole was 4 negative and 1 positive, which looks like Omeprazole might decrease risk somewhat. And rabeprazole was one negative and zero positive.

The only PPIs that showed a clear tendency to decrease risk were lansoprazole and maybe omeprazole. As for the Almario study, they did not provide the data on types of PPI. And lansoprazole is not a very common type of PPI. Perhaps, in the larger Almario study most types of PPI, while lansoprazole might not have done so. We don’t know, as we don’t have the data broken down by PPI. But with 11 out of 12 lansoprazole users testing negative for Covid-19, that medication is worth further study.

However, for the time being, it is clear that most, if not all, PPIs increase risk of infection with Covid-19 [5], whereas famotidine and perhaps other H-2 blockers decrease risk of death and of the need for oxygen therapy [1, 2]. The other consideration is whether H-2 blockers might perform better when paired with an H-1 blocker [3]. That is an interesting hypothesis, which was not supported or refuted by the one study (Hogan) on that point.

Update: 6. Ramachandran

Another study on this topic, “Prehospitalization Proton Pump Inhibitor (PPI) use and Clinical Outcomes in COVID-19,” found increased risk with use of PPIs. “Mortality among PPI-users was 2.3 times higher than non-users, along with 2.5 times higher risk of mechanical ventilation.”[8] Given that there are two studies which found risk increase, and the study which find risk decrease was smaller than either of the other two, the conclusion that there is a risk increase seems more likely. It may be that Blanc’s results were due to the use of lansoprazole by a large percentage of their population.

Update: 7. Seung Won Lee

“Among patients with confirmed COVID-19, the current use of PPIs conferred a 79% greater risk of severe clinical outcomes of COVID-19, while the relationship with the past use of PPIs remained insignificant. Current PPI use starting within the previous 30 days was associated with a 90% increased risk of severe clinical outcomes of COVID-19.” [9] Link to the Study

The Lee study included over 130,000 patients. The results are quite clear that taking PPIs while sick with Covid-19 increases risk of a severe outcome, including death.

Ronald L. Conte Jr.
Covid.us.org
Note: the author of this article is not a doctor, nurse, or healthcare provider.

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1. Freedberg, Daniel E., et al. “Famotidine use is associated with improved clinical outcomes in hospitalized COVID-19 patients: A propensity score matched retrospective cohort study.” Gastroenterology (2020).
https://www.sciencedirect.com/science/article/pii/S0016508520347065

2. Janowitz, Tobias, et al. “Famotidine use and quantitative symptom tracking for COVID-19 in non-hospitalised patients: a case series.” Gut (2020).

3. Hogan, Reed B., et al. “Dual-Histamine Blockade with Cetirizine-Famotidine Reduces Pulmonary Symptoms in COVID-19 Patients.” medRxiv (2020).

4. Blanc, Frederic, et al. “Interest of Proton Pump Inhibitors in Reducing the Occurrence of COVID-19: A Case-Control Study.” (2020).
https://www.preprints.org/manuscript/202005.0016/download/final_file

5. Christopher V. Almario; William D. Chey, MD; Brennan M.R. Spiegel. “Increased Risk of COVID-19 Among Users of Proton Pump Inhibitors.” American Journal of Gastroenterology, 2020.

Click to access AJG-20-1811_R1(PUBLISH%20AS%20WEBPART).pdf

7. McPadden, J. et al. “Clinical Characteristics and Outcomes for 7,995 Patients with SARS-CoV-2 Infection.” medRxiv (2020).
https://www.medrxiv.org/content/10.1101/2020.07.19.20157305v1

8. Ramachandran, Preethi, et al. “Prehospitalization Proton Pump Inhibitor (PPI) use and Clinical Outcomes in COVID-19.” medRxiv (2020).
https://www.medrxiv.org/content/10.1101/2020.07.12.20151084v1

9. Lee, Seung Won, et al. “Severe clinical outcomes of COVID-19 associated with proton pump inhibitors: a nationwide cohort study with propensity score matching.” Gut (2020).