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Doxycycline and Nitazoxanide as a Candidate Immunomodulatory Combination for the Early Management of Ebola Disease Caused by Bundibugyo Virus

Submitted:

07 November 2026

Posted:

09 November 2026

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Abstract
As of 5 November 2026, Bundibugyo virus disease in the Democratic Republic of the Congo had produced 10,741 confirmed cases and 5,230 deaths, with close to two of every three deaths in an earlier WHO reporting interval occurring in communities rather than treatment centres. No vaccine or treatment is approved for this species, and the agents in trials are monoclonal antibodies and direct-acting antivirals. In 2021 I proposed reclassifying COVID-19, Ebola virus disease and Nipah virus infection as a novel acute onset immune dysrhythmia syndrome. Read through it, the pathology now described in Bundibugyo-infected macaques points to two arms: fatal animals showed a myeloid hyperinflammatory profile with raised interleukin-6 and myeloperoxidase, survivors transcripts of an intact T cell response. Basing on that convergence I propose doxycycline and nitazoxanide as an early immunomodulatory combination, each acting on a different arm. Doxycycline inhibits matrix metalloproteinases at exposures achievable in man, and nitazoxanide amplifies the RIG-I and PKR arm the virus suppresses. To be noted that none of this establishes efficacy in Bundibugyo disease. What it offers is a mechanism worth testing in two licensed, oral, inexpensive drugs on the shelf, with the host-directed concentration still unmeasured. I therefore ask for species-specific work: activity in relevant cells and in the macaque model, the unbound concentration-response relationship, and a two-by-two factorial evaluation, preclinical and clinical, powered for the interaction. I strongly believe the search for safe immunomodulators is the one most likely to end in a drug available on the day it is needed.
Keywords: 
Bundibugyo virus
;  
filovirus
;  
host-directed therapy
;  
drug repurposing
;  
doxycycline
;  
nitazoxanide
;  
acute immune dysrhythmia syndrome
;  
type I interferon
Subject: 
Medicine and Pharmacology  -   Epidemiology and Infectious Diseases
As of 5 November 2026, from data to 4 November, the outbreak of Ebola disease caused by Bundibugyo virus, a member of the genus Orthoebolavirus, in the Democratic Republic of the Congo had produced 10,741 confirmed cases and 5,230 deaths, a crude case fatality close to 49%, across eight provinces [1], with nine confirmed cases in Kenya and one imported case in Nigeria [2]. To be noted that these counts are revised as data are harmonised, the 31 October situation report having added 314 deaths in Ituri that the reports of 1 and 2 November did not reflect [3]. Of the 482 deaths reported in the WHO update of 23 October, 307 were in communities and 175 in treatment centres [2]. That proportion points to delayed access to care, and it shapes what any useful therapy must be.
No approved vaccine or specific treatment exists for Bundibugyo virus disease, and a pivotal phase 2/3 vaccine trial enrolled its first participants on 23 October 2026 [2]. The agents under evaluation are monoclonal antibodies and direct-acting antivirals, each unlicensed for this species or unavailable at scale. Noteworthy, none is a host-directed immunomodulator. A cold-chain biologic rarely reaches a patient dying in a village, and the community deaths above show how many never reach the places where such a product is held.
In 2021, I proposed that COVID-19, Ebola virus disease and Nipah virus infection be reclassified as a novel acute onset immune dysrhythmia syndrome, driven by monocytic dysrhythmia and a disturbed Th1/Th2 balance with interleukin-6 implicated, and that immunomodulators could manage them effectively [4]. That proposal came from real-life practice managing COVID-19 patients while studying other viruses as well, without species-specific filovirus data, which have now arrived.
The natural history of Bundibugyo virus in 21 cynomolgus macaques was characterized this year in a preprint not yet peer reviewed [5]. Eight of the twelve animals followed to the study endpoint died between days 9 and 17, and four survived to day 28. Fibrin was deposited in the liver by day 4, before any clinical sign, and thrombocytopenia was present in all three animals sampled at day 8. Fatal animals showed a myeloid-driven hyperinflammatory profile with raised interleukin-6 and myeloperoxidase, while survivors showed transcripts of an intact T cell response. Viral antigen was present in endothelial cells, and claudin-5 was focally lost from inflamed cerebral vessels in a fatal animal. Peak circulating viral RNA did not separate survivors from fatal animals, although peak infectious virus titres were significantly lower in the survivors. Circulating RNA is therefore a poor guide to outcome in this model. Infectious burden and the host response both appear to matter. These remain associations in a small cohort rather than demonstrations of causality, yet they fit what my framework claims, that dysregulated host responses contribute substantially to outcome.
Moreover, timing may matter as much as the choice of drug. The incubation period runs from two to 21 days and early symptoms are non-specific, which delays detection and allows progression to organ dysfunction and hemorrhage [2], and death in the macaque model followed between days 9 and 17 [5]. A window therefore plausibly exists, opening before the patient looks severely ill, and whether treating within it changes outcome is itself what must be tested. This is the principle behind Kelleni’s protocol for the early management of COVID-19 and other viral infections [6], where the object is to abort progression aiming at preventing organ failure.
Basing on that convergence, I wish to propose doxycycline and nitazoxanide as an early immunomodulatory combination. The logic is the one I have applied to azithromycin in the early management of COVID-19 [6]: an agent licensed as an antimicrobial may be selected for properties unrelated to its antimicrobial spectrum, provided the clinician is clear which indication is treated. So used, they would be given in addition to, and never in place of, the supportive care WHO now sets out for filovirus disease, which covers all five filoviruses known to cause human disease, including this one [7], and whatever presumptive antibacterial cover a severely ill patient requires. WHO suggests presumptive broad-spectrum antibiotics where sepsis or bacterial co-infection is suspected, without delay [7], and doxycycline is not adequate cover on its own for that purpose.
Using a tetracycline this way has precedent. Fredeking and Ignatyev disclosed tetracycline-based modulation of inflammatory responses in hemorrhagic viral infections in patent WO2000064479A1 [8], whose European application was withdrawn in 2003, and the same programme produced the dengue studies set out in the table below and an unverified 2014 conference abstract on experimental filovirus findings whose full methods and dataset are not available. To be noted that these are one programme rather than independent replication, and that I have found no later independent validation in filovirus disease. In dengue itself, an independent randomized, double-blind, placebo-controlled trial of doxycycline in 61 patients found no difference in clinical course or hospitalization, and no significant change in interleukin-6 or TNF. No patient died in either arm, so that trial could neither show nor exclude an effect on mortality, and its authors judged the sample too small to settle the question [9]. It did not reproduce the cytokine findings of the 2015 study in the table, and it could not test its mortality finding, so both stand unreplicated. A second independent trial, open-label, randomized 69 patients to doxycycline 100 mg twice daily for five days or to standard care alone, but could process day-five samples from only 45, and in those found ferritin and C-reactive protein falling further with doxycycline, at p equal to 0.006 for each, with no significant difference in interleukin-6 or TNF [10]. Interleukin-6 fell steeply in both arms, from 21.7 to 1.9 picograms per millilitre on doxycycline and from 15.1 to 0.6 without it, and the TNF difference did not reach significance at p equal to 0.094. Ferritin also started higher in the doxycycline arm, and clinical outcomes were not studied. Neither independent dengue trial reproduced the earlier significant interleukin-6 or TNF findings. None of these dengue trials was large enough to settle the question, and none was conducted in a filovirus disease, which is where the question I raise actually sits.
Noteworthy, two proposals have partly preceded mine. Hendricks and colleagues suggested minocycline, a related tetracycline, as adjunctive anti-inflammatory therapy in Ebola virus disease and the post-Ebola syndrome [11]. Theirs was a proposal resting on a biomarker comparison and on the dengue mortality work, which had used doxycycline. However, they did consider timing, holding that the anti-inflammatory benefit might be greater when treatment starts early. Similarly, Schiffmann has proposed nitazoxanide, with ivermectin as an exploratory adjunct, for monitored emergency use in the present outbreak, basing on the same interferon data [12]. I do agree with the direction of both, and I take this convergence as support rather than as a competing claim. What I wish to add starts from the framework I set out in 2021 [4]. Read through it, the immunopathology now described in macaques points to two drugs rather than one: doxycycline against the pathological myeloid arm, nitazoxanide for the type I interferon response that the virus actively suppresses. Neither earlier proposal could use that pathology, neither paired the two drugs, and doxycycline has not been proposed in this species. Whether combining them helps, adds nothing, or interferes, is unknown, and that is itself a question for testing. Its object is treatment within an early window rather than adjunctive use at any stage.
Table. Doxycycline and nitazoxanide against the processes implicated in Bundibugyo virus disease.
Process Evidence What it does not establish
Myeloid hyperinflammation with raised interleukin-6 Doxycycline (human randomized trials): in 114 patients with dengue randomized to doxycycline, tetracycline or supportive care, interleukin-6, interleukin-1 beta and TNF fell while interleukin-1 receptor antagonist rose [13]; in 231 patients with dengue hemorrhagic fever randomized to doxycycline, mortality was 11.2% against 20.9% with lower interleukin-6 and TNF [14] For the 2011 study, biomarker change only, with no clinical endpoint. For the 2015 trial, a 9.7 percentage point absolute difference that was borderline at p = 0.05 and not shown to be mediated by cytokine change. For both, a different virus with different immunopathology, shared investigators, and no mortality benefit demonstrated in this disease
Endothelial barrier failure with claudin-5 loss Doxycycline (human randomized trial, plus in-silico docking, cell culture and mouse model): docking predicted binding at the matrix metalloproteinase-9 active site with chelation of its catalytic zinc, while experiment showed reduced enzyme activity, preserved tight junction localization against interleukin-1 beta, and microvascular hyperpermeability reduced by 25% in mice [15]; in patients undergoing cardiopulmonary bypass, a randomized trial reported reduced endothelial glycocalyx shedding through matrix metalloproteinase inhibition [16] The protein preserved was ZO-1, not claudin-5; the 25% figure is blood-brain barrier permeability in a mouse traumatic brain injury model rather than an effect measured in infection; whether matrix metalloproteinase-9 drives endothelial injury in this infection is assumed; the human trial measured shed glycocalyx markers during elective cardiac surgery, with the drug given before the insult, and measured neither claudin-5 nor any effect in an infection
Type I interferon suppression by VP35 and VP24 Nitazoxanide (cell culture, plus a human randomized trial in influenza): amplified the RIG-I and PKR (protein kinase R) arm of innate antiviral signaling and suppressed Ebola virus in A549 human lung epithelial cells, the effect falling 10.5-fold when PKR was silenced [17]; 600 mg twice daily shortened median time to symptom alleviation by about 21 hours in laboratory-confirmed uncomplicated influenza [18] The virus tested was the Zaire species, not Bundibugyo, in A549 lung epithelial cells at 20 to 40 micromolar; these concentrations have not been shown to be achievable as unbound drug at the sites of infection, and the influenza population was outpatients with uncomplicated disease, and no clinical endpoint in any filovirus disease
Importantly, what is known about doxycycline in humans justifies studying and testing it here. Doxycycline hyclate 20 mg twice daily is approved in the United States as an adjunct to scaling and root planing in adult periodontitis, acting through matrix metalloproteinase inhibition at sub-antimicrobial exposure, and was, when Caton and Ryan reviewed the field in 2011, the only such inhibitor approved for human use [19]. Metalloproteinase inhibition therefore occurs at achievable concentrations, though whether modulation of interleukin-6 or TNF does is unknown, and a prolonged low-dose dental regimen does not define an acute systemic one. Moreover, that inhibition has been shown to protect the endothelium in patients. In a randomized trial in people undergoing cardiopulmonary bypass, doxycycline reduced endothelial glycocalyx shedding through matrix metalloproteinase inhibition [16]. To be noted that this was a planned surgical insult rather than an infection, and that dosing before a scheduled injury is not the same as treating an illness already under way, so it is not the timing I propose. What the trial does show is that doxycycline can reduce metalloproteinase-driven shedding of the human endothelial glycocalyx, which is the step that had rested on animals alone.
However, the personalized medical approach is always crucial. Profuse vomiting may defeat enteral administration, and doxycycline may cause esophageal ulceration, which deserves attention in a recumbent patient. Moreover, Bundibugyo infection produces hepatitis [5], so hepatic tolerability needs monitoring. Noteworthy, tetracyclines remain restricted in pregnancy, a group in whom a systematic review found maternal mortality of 72% among 274 women with Ebola virus disease [20]. Nitazoxanide is the half of the pair that remains available there. Its label carries no comparable restriction, and animal reproduction studies found no teratogenicity or fetotoxicity at exposures 30 times the maximum recommended human dose in rats and twice it in rabbits by body surface area, though that same label records no data in pregnant women [21]. That absence is not quite complete. In a real-world series I reported nitazoxanide given to two pregnant patients with COVID-19, one in the ninth week of gestation, confirmed by PCR, who went on to deliver a healthy newborn, and one in the thirty-fourth, not laboratory-confirmed and given other medication alongside, who improved within the five-day course [22]. Two patients cannot establish safety, and I present them as experience rather than as evidence. So for a pregnant patient I propose the nitazoxanide arm alone, and I would leave doxycycline to a clinical judgment that a maternal mortality of 72% ought to prompt rather than foreclose. There is precedent for making that judgment rather than avoiding it. For Rocky Mountain spotted fever the Centers for Disease Control and Prevention holds that doxycycline should be used whenever possible in patients of all ages, including pregnant women, with the potential risks and benefits put to them [23]. That is an established therapy in a disease where it works, which is not the case here, so what carries over is the reasoning and not the drug. Children are different. Short-course doxycycline is now accepted in young children for selected serious infections, rickettsial disease above all, and nitazoxanide is licensed in the United States from the age of one as an oral suspension for diarrhoea caused by Giardia or Cryptosporidium, though the 500 mg tablet is labelled from the age of twelve [21]. Stewardship applies wherever an antibacterial is given for a non-antibacterial purpose. Doxycycline has been given to adults for more than half a century and nitazoxanide for over two decades, and I argue that their safety is known as no investigational filovirus agent’s is. Yet, that record comes from other diseases, still waiting this one.
Interestingly, nitazoxanide belongs in the same proposal. Ebola viruses suppress type I interferon, VP35 binding PACT, an activator of the kinase PKR, and disrupting that antagonism attenuates the virus in animals. Nitazoxanide suppressed Ebola virus, the Zaire species, in A549 human lung epithelial cells by amplifying that arm, the effect falling 10.5-fold when PKR was silenced [17]. Its clinical effect in another human viral illness is not theoretical, as the influenza trial in the table shows [18], even though that trial cannot say which mechanism produced it. In my own practice in Egypt I’ve used generic nitazoxanide at 500 mg twice daily, the approved adult dose, as an early immunomodulator within Kelleni’s protocol in COVID-19, respiratory syncytial virus and influenza [6]. Taken together, doxycycline may damp the pathological myeloid response while nitazoxanide may restore the protective one, which is what correcting an immune-dysrhythmia should mean rather than blanket suppression.
Noteworthy, four randomized trials of nitazoxanide in another viral disease bear on the question I raise, and across them the result tracks how ill the patient was. In 405 of 498 patients randomized while hospitalized with COVID-19 pneumonia and needing oxygen, 500 mg three times daily did not significantly reduce intensive care admission, the primary endpoint, with a hazard ratio of 0.68 and a confidence interval from 0.38 to 1.20 [24]. Death rates did not differ either. Yet, clinical status improved, oxygen requirement fell, patients went home sooner, and C-reactive protein, D-dimer and ferritin were lower by day 7. A pilot of 50 patients in moderate disease, 25 to each arm, reported superiority to placebo [25]. In milder disease the primary endpoints were not met, and the secondary findings were thinner rather than absent. In 392 ambulatory patients symptom resolution did not differ and none of C-reactive protein, interleukin-6, interleukin-8, interleukin-1 beta, TNF or interferon gamma moved, though viral load fell significantly [26]. In 379 outpatients time to sustained recovery did not differ, while return to usual health improved in a prespecified mild stratum and progression to severe illness occurred in 1 of 184 against 7 of 195, a difference the trial was not powered to establish [27].
A meta-analysis of five blinded placebo-controlled trials put progression to intensive care or ventilation at a risk ratio of 0.63 with a confidence interval from 0.38 to 1.04, found white cell count, lactate dehydrogenase and D-dimer significantly lower, with the other inflammatory markers not reaching significance, and concluded that there was no evidence of clinical benefit in mild or moderate disease [28]. To be noted that an interval from 0.38 to 1.04 runs from a 62% reduction in relative risk to a 4% increase. It is therefore compatible with substantial benefit and with none, and what that pooled estimate shows is an absence of statistical significance rather than an absence of effect. No heterogeneity was detected for that endpoint. That neither supports nor undermines what I am suggesting, since heterogeneity is computed separately for each outcome and severity was never tested as a modifier of any of them. And the markers did not all behave alike. Interleukin-6, interleukin-8 and C-reactive protein each pooled in favour of nitazoxanide without reaching significance, and differences between the trials accounted for 89%, 77% and 94% of the variation in them, against none at all for the cell counts and D-dimer. Variation of that size has several possible sources, among them sampling time, assay, dose and baseline concentration, and with so few trials the estimates are themselves imprecise, so I do not present it as support for my reading. What I take from it is narrower. Those pooled estimates are too imprecise to close the question, and that analysis did not test severity or baseline inflammation as modifiers of the effect. That is what I am asking for. I have used the drug early in that disease within Kelleni’s protocol and published that use [29].
I read that pattern across the four trials as a severity-dependent effect, and I hold it as a hypothesis rather than a finding. One measurement inside those trials bears on it. In the ambulatory trial the reported baseline median was zero for interleukin-6, interleukin-1 beta, TNF and interferon gamma before any drug was given, TNF was reported as zero in at least three quarters of both arms, and C-reactive protein stood at 6.0 and 4.5 mg per litre [26]. Where there is little measurable inflammation there is little to reduce, which is why I do not read the flat cytokines in that trial as evidence against the mechanism. To be noted that this argument reaches only so far. A median of zero in that trial means only that at least half its readings came back as zero, which may mean the cytokine sat below what the assay could detect rather than that it was absent, and at least a quarter of those patients did have measurable interleukin-6, its upper quartile reaching 4.10 and 8.34 in the two arms, in the picograms per decilitre that trial reports. Interleukin-8 is the exception, its baseline medians not zero but 2.79 and 5.51, and after five days the arms stood at 2.73 and 2.70, with no significant difference between them. That is the observation this reading does not account for, and I record it rather than set it aside. The trials also differ in what mattered besides severity. Treatment began within 72 hours of onset in the outpatient trial [27], at a median of five days in the ambulatory trial [26] and at a median of seven in the hospitalized trial [24], and no comparison between them can separate timing from severity, dose or endpoint.
I then put this reading through the same three tests I applied to the dengue programme above: whether the finding is independent of one investigator group, whether the mechanism was measured rather than assumed, and whether the numbers carry the claim. It does not come through all three intact. The markers that moved in the trial of patients needing oxygen [24] are acute-phase reactants and markers of injury and coagulation rather than the cytokines my framework names, and interleukin-6 was not measured in that trial at all. A falling C-reactive protein may equally mark a patient who was already recovering, which would make it a consequence of improvement rather than evidence that the drug corrected anything, and no trial has tested that distinction. And the hospitalized trial [24] and the ambulatory trial [26] come from the same investigators, one of whom is also an author of the pilot [25]. Three of these four trials therefore overlap in authorship, and the two ends of that severity range are not an independent replication. So this is what I am asking to have tested, and it rests on the baseline measurements above rather than on any comparison between trials. None of this is filovirus evidence and I don’t offer it as such.
Noteworthy, host responses here are both pathological and protective, as the macaque survivors showed. The WHO therapeutics advisory group judged in June 2026 that the available evidence was insufficient to select host-directed candidates for trials, and it warned that some immunomodulatory agents may prove detrimental, including on viral replication [30]. Its grounds are broader than the choice of drug: the group asked for human pathogenesis data, for evidence on timing, and for patient selection, and each of those requirements applies to the two drugs proposed here as much as to any other. The caution itself is not new to me. I set it out for dexamethasone in COVID-19 in 2021, arguing against routine glucocorticoid use, restricting it to selected severe and critical patients, and urging physicians in developing countries not to give it in mild to moderate disease [31]. Corticosteroids suppress the response in bulk, and in a disease whose survivors keep an intact T cell response that is a real hazard. They are not what I am proposing. Immunomodulators are not one class carrying one risk. They act on different targets, and the target decides whether the effect helps or harms. I have chosen these two because each acts on a defined arm, because one of them amplifies innate antiviral signalling instead of suppressing it, because their human risks have been described over decades, and because a treatment unit in Ituri can actually give them.
Searching for the safe immunomodulators is sound practice in every epidemic and pandemic threat, and I strongly believe it is the search most likely to end in a drug that is available on the day it is needed. In an epidemic the considered opinion of experts, working from the pathogenesis data that exist rather than from the data we would wish to have, is itself a way of caring for precious lives. I applied that principle in Kelleni’s protocol [6]. Thus, caution of this kind should shape the search rather than close it.
A therapeutic trial is now open. The WHO-sponsored PARTNERS platform began enrolling patients of any age with confirmed Bundibugyo disease in the Democratic Republic of the Congo on 2 July 2026, testing the monoclonal antibody MBP134 and remdesivir, singly and together, against a background of optimized supportive care [32]. The vaccine work is a separate study: WHO reported on 4 November that two Bundibugyo-specific candidates have been recommended for addition to the Tumaini ring-vaccination trial, pending national approvals, alongside the arm already evaluating Ervebo, the vaccine whose efficacy was established against Zaire ebolavirus and which is now being assessed against this one [33]. What matters for this proposal is that PARTNERS is a platform, and it is already being added to: the same release records that maftivimab will soon enter the trial, with a complementary post-exposure prophylaxis study of obeldesivir under way. Neither addition is a host-directed immunomodulator, so the gap I am describing has not closed. I strongly suggest that doxycycline and nitazoxanide belong in that assessment, and I wish to see them in it while the platform is still running. What I am asking is that the two proceed together: the species-specific work begun now, and the criteria that would admit this pair as an arm set out now, so that entry becomes a decision the platform can take within this outbreak rather than after it. A drug given inside a trial is monitored and its outcome is recorded and that is an argument for opening trials quickly rather than waiting.
That work needs activity against Bundibugyo virus in relevant cells and in the macaque model, and measured tissue exposure of doxycycline and of tizoxanide, the active metabolite into which nitazoxanide is converted. It also needs a two-by-two factorial evaluation, each drug alone, the two together and neither, so that the pair is tested as a question in its own right, initially in those preclinical models and powered to assess the interaction. Dosing must begin at defined points, from post-exposure before any sign appears to the earliest detectable illness and on to established disease, so that timing is tested rather than assumed. In the animal studies the primary endpoint is survival, not a cytokine.
Measured exposure, which I have just listed among those requirements, is the hardest part of what I am proposing. No measurement I have found relates unbound tizoxanide at an achievable human dose to any host-directed readout in the cells I am targeting. To be noted that the number I am asking for is not the antiviral one. The 20 to 40 micromolar range in the table is the concentration at which nitazoxanide suppressed Ebola virus in cell culture, and I’m not proposing the drug as an antiviral in this species, so that’s not the figure that has to be met. That suppression was itself host-mediated, so the number is not irrelevant, but it came from a cell line with viral replication as the readout rather than from the cells I am targeting, and the compound in those experiments was nitazoxanide itself rather than the tizoxanide that circulates in patients. Instead, what has to be met is whatever concentration modulates those cells, and nobody has established it. A host-directed agent does not have to reach the virus; it has to reach the cells that are responding badly. That is a different requirement from inhibiting viral replication, not necessarily a lesser one, since the host-directed concentration may prove lower or higher and only an experiment will say which. Nor can plasma concentrations alone settle that question, because the parent drug is not detectable there, the circulating tizoxanide is almost entirely protein bound [21], and the macrophages and endothelium that matter in this disease are not all in the blood. So the measurement I am asking for is the unbound concentration-response relationship for the host-directed effect, established first in human cells ex vivo and then set against what an achievable dose delivers, rather than the assumption that it must equal the antiviral one.
Most importantly, there remains the patient no trial will reach. Close to two of every three deaths in that reporting period occurred in communities rather than treatment centres [2]. That is where the dying are, and a proposal that stops at the door of a treatment unit will not reach them. Paragraph 37 of the 2024 Declaration of Helsinki sets conditions for the use of an unproven intervention in an individual patient where approved options are inadequate or ineffective and enrolment in a clinical trial is not possible. It grants no permission of its own. It requires expert advice to be sought first, the possible risks, burdens and benefits to be weighed, informed consent to be obtained, and data to be recorded and shared when appropriate. Such use must never be undertaken to circumvent the protections for research participants, it must avoid compromising clinical trials, and the intervention should afterwards be made the object of research evaluating safety and efficacy [34]. Those last conditions are not constraints I resent. They are the same thing I am asking for. The WHO framework for monitored emergency use of unregistered and investigational interventions is the operational counterpart [35]. Neither instrument authorizes a treatment programme on its own, and neither displaces national regulation, ethics review or clinical governance. For the patient who dies in a community rather than a treatment centre, they are nonetheless the only doors that exist. I strongly believe that an oral, inexpensive drug whose human risks are known, with a defined mechanistic rationale, offered early under those protections and with the outcome of every patient reported, is a better answer than the nothing that is at present directed at the disease killing that patient. The patient comes first. The supportive care WHO sets out is never withheld [7], and the trials I am asking for should open alongside that care rather than after it. I urge both soonest.
The immunological and endothelial evidence now available identifies a specific, inexpensive and testable hypothesis for the early management of this disease, with two drugs already on the shelf. Should it be confirmed, precious lives might be saved, as wished. Should it not, what will have been spent is the testing of two drugs whose human risks have been described for decades and whose cost any ministry can meet, along with the trial capacity and the stewardship margin that testing consumes, and I will keep looking.

Conflicts of Interests

The author declares no financial interest in doxycycline, nitazoxanide, or any product named here, and holds no commercial rights in the management protocol bearing his name cited above. The author is the founder of Kdemic, an academic writing platform. This has no interest in the subject matter of this correspondence.

Author note

The author is a clinical pharmacologist and physician working at the College of Medicine, Minia University as a lecturer of pharmacology (equivalent to assistant professor), and a research fellow at INTI International University. Since April 2020 he has published, as sole author, a series of peer-reviewed papers proposing early, affordable repurposed treatment of COVID-19, including the nitazoxanide-based protocol cited here. ScholarGPS ranks him a Highly Ranked Scholar in the top 0.05% in COVID-19, first in Egypt and 110th worldwide over the prior five years, accessed October 2026, and he has appeared in the Stanford University and Elsevier list of the world’s top 2% most-cited scientists in four consecutive editions, 2022 to 2025.

Declaration of generative AI

Claude (Anthropic), ChatGPT (OpenAI) and Manus (Manus AI, Butterfly Effect Pte. Ltd.) were used under my guidance to search for, retrieve and cross-check relevant scientific literature, to assist in its selection and synthesis, to assist in drafting this manuscript and in editing its language, and to provide critical review of successive drafts. All AI-assisted output was critically reviewed, corrected where necessary, and approved by me before inclusion, and every reference was verified against its source. The work is mine throughout: what to pursue, what to accept, what to discard and what to conclude. I take full responsibility for the accuracy and integrity of the final manuscript.

Funding

None.

Acknowledgments

This work was carried out without a research team and without institutional support. Neither this work nor my previous work received any fund or support from my Egyptian institution. I used AI assistants in place of the literature-filtering and language-editing support I do not have, and they saved me time and effort that my clinical, academic, administrative and family duties leave me little of. I record this with gratitude and without embarrassment. For researchers working as I do, I suggest such tools are becoming a question of access rather than convenience.

References

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