Kelleni’s protocol incorporating non-steroidal anti-inflammatory drugs and nitazoxanide to early manage dengue virus disease: An antiviral silver bullet

Abstract

The current recommendation to avoid non-steroidal anti-inflammatory drugs (NSAIDs) in the management of dengue virus disease (DVD) is scientifically considered of very low to low certainty, despite being widely adopted worldwide. The same recommendation, initially made during the coronavirus disease 2019 (COVID-19) pandemic, was subsequently proven incorrect. In this clinical report, we present evidence, for the first time globally, from a real-life practice that NSAIDs may actually be lifesaving in the early management of DVD as they have proved to be in COVID-19. Moreover, we propose that the personalized immune-modulatory Kelleni’s protocol, which includes nitazoxanide as a key component, can be safely and effectively used to manage various separate or concomitant viral infections and co-infections, including DVD. Importantly, this article contributes to the current medical knowledge in the global pursuit of a safe and effective broad-spectrum antiviral protocol that can be used to early manage multiple highly infectious viruses. However, it’s crucial that sufficiently powered controlled randomized clinical trials be conducted to thoroughly assess and evaluate the safety of NSAIDs in the early management of DVD as well as the efficacy of nitazoxanide with or without NSAIDs in its management.

Key Words: COVID-19; Dengue; Influenza; Kelleni’s protocol; Norovirus; SARS-CoV-2; Respiratory syncytial virus

Core Tip: Dengue virus disease (DVD) is estimated to affect up to 400 million people globally every year. The World Health Organization considers it the fastest growing mosquito-borne infection, and recently the infection has surpassed its historic transmission area. Unfortunately, there is no approved specific antiviral therapy to manage it. In this article, we argue that non-steroidal anti-inflammatory drugs and Kelleni's antiviral protocol could be easily repurposed to manage early DVD and prevent its progression to dengue hemorrhagic fever and death, as it has done with severe acute respiratory syndrome coronavirus 2 and other viruses. Kelleni's protocol has proven to be life-saving for patients of all ages in real-world practice, and it could be seen as an ideal empiric broad-spectrum antiviral Holy Grail that is much needed in our clinical practice.

INTRODUCTION

Dengue virus disease (DVD), which includes dengue fever, dengue hemorrhagic fever and dengue shock syndrome, is caused by the dengue virus. As a member of the Flaviviridae family, it represents the fastest-growing mosquito-borne infection according to the World Health Organization (WHO). Notably, dengue virus can be co-transmitted with other viruses such as Zika and Chikungunya viruses, and cases of human co-infections have been reported[1-3].

DVD has spread to at least 129 countries, with over 100 tropical and subtropical countries are considered endemic or hyper-endemic. It has an estimated global annual incidence of 400 million infections of which 100 million cases become symptomatic, mostly self-managed, under-reported or misdiagnosed and only 5 million suspected serious infections were officially reported to the WHO in 2023. Alarmingly, in 2023, the number of DVD cases has up-surged globally as compared to the average reported in the past five years and the disease had further spread beyond its historical transmission areas[4]. Furthermore, DVD is considered an evolving threat to the remaining naïve countries, possibly due to climate change leading to changing distribution of the vector e.g., El Nino phenomena and/or viral evolutionary mutations[5]. For instance, locally transmitted DVD cases have been confirmed in France since 2010, and the number of domestic French DVD infections in 2022 exceeded the sum of the reported infections in the previous ten years. Moreover, in 2023, locally acquired dengue cases were officially reported in France, Italy and Spain.

Importantly, half of the world population is currently considered at risk of contracting DVD. Annually, 400000 cases of dengue hemorrhagic fever are reported with around 40000 of deaths especially among high risk groups such as children and geriatric patients, due to serious complications like internal or external hemorrhage and shock. Unfortunately, there is no specific antiviral drug available to manage DVD and only symptomatic and supportive treatment is provided. Currently, paracetamol (acetaminophen) is recommended for the symptomatic management of pain and fever, while non-steroidal anti-inflammatory drugs (NSAIDs) are currently recommended to be avoided in DVD management[2].

Furthermore, many researchers all over the world have tried to distinguish coronavirus disease 2019 (COVID-19) from other viral infections such as influenza, parainfluenza, respiratory syncytial virus (RSV), human metapneumovirus, and dengue in order to administer the proper pharmacotherapy[6,7]. They have demonstrated how this important differentiation can be very challenging not only clinically but also in terms of radiological[8] or serological investigations, due to possible cross reactivity between dengue virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies leading to occasional false positive serology tests[9]. However, these and other insightful remarks[10] remained inadequate in numerous real-world clinical situations. Additionally, co-infection with more than one viral infection is also another real-life medical challenge[7] which can increase the severity of the clinical condition[11] and lead to more complications, such as the risk of intensive care unit admission and mechanical ventilation[12].

Therefore, the search for a safe, generic and cost-effective broad-spectrum antiviral protocol that can be used for early empiric management of separate of simultaneous multiple highly infectious viruses is continuing to be considered a noble quest for a medical holy grail. We strongly suggest that these criteria are fully achieved in the Egyptian Kelleni’s immune-modulatory protocol.

This article aims to demonstrate how the Egyptian and African Kelleni’s antiviral protocol that was initially safely and effectively used to manage COVID-19 while repurposing safe and cost-effective generic drugs and later evolved to manage other viruses[6] has also a promising potential to safely manage DVD.

Dengue outbreak in Qena, Egypt

Egypt is classified as a dengue endemic country. However, most the Egyptian provinces, including Qena Governorate, had seldom experienced a dengue outbreak and the general local medical awareness of its symptoms was very limited. On July 18, 2023 the Egyptian Ministry of Health has officially acknowledged that the cause of an outbreak in some villages in Qena Governorate, Upper Egypt, was DVD. This outbreak was characterized by symptoms such as high fever, headache, severe musculoskeletal pain, severe malaise, vomiting, diarrhea and some respiratory manifestations resembling SARS-CoV-2 infection. Noteworthy, these villages experienced DVD for the first time, unlike other areas in Egypt. However, this official announcement confirming the presence of DVD, at least in “some samples” as described, with evidence of its local transmission came after an earlier denial followed by reluctance to acknowledge the diseases which was described as a “strong flu” and the physicians managed those patients as they do with COVID-19. Moreover, to the best of my personal investigation, the characteristic dengue rash, which is known to occur in almost half of the cases, whether in the acute or the recovery phases was not frequently observed during this outbreak.

Meanwhile, there has been an unusual rise in cases of “atypical viral” pneumonia, although not in an alarming number as encountered in the Qena Governorate outbreak, encountered elsewhere, to be noted that since the emergence of the BA.2 “stealth” variant in early 2022, the local rapid antigen tests were commonly showing negative results and these samples are, at least unofficially, required to test positive before an “official” diagnosis of COVID-19 is made, and before subsequent advanced molecular investigations being (or not) later performed. Notably, we suggest that these described “atypical viral” pneumonia cases are most likely due to the SARS-CoV-2 EG.5 variant of interest, as later revealed and named globally, to be noted that the first “officially” reported Egyptian EG.5 cases were announced on August 22, 2023. Moreover, we also suggest this announcement to be late and unnecessary, as Egypt and Africa have been free from COVID-19 obsessions and mandates thanks to it’s the early COVID-19 management and the antiviral Kelleni’s protocol[6,13,14].

Surprisingly, the official statement from the Ministry of Health mentioned the detection of the relatively scarce EG.5.2 that was detected, rather than the EG.5.1 variant which was the one of global interest due to its potentially higher effective reproduction number. When we sought clarification, we received a private confirmation that no mistake had been done and we wondered if the detected genetic sequence could be shared in public, but no further replies were received.

Taken together, a dengue outbreak early diagnosis can be very challenging, particularly in previously naïve areas and in the midst of the emergence of new SARS-CoV-2 variants with atypical tropism and unusual clinical manifestations[15].

Using NSAIDs and Kelleni’s protocol to early manage dengue fever

We would like to report that hundreds of Egyptian patients of all ages, including some officially confirmed DVD patients, in the affected villages of Qena Governorate were safely and effectively early managed as COVID-19 cases using ibuprofen or other NSAIDs, along with broad spectrum antimicrobial drugs such as nitazoxanide and/or azithromycin (Kelleni’s protocol), to manage their high grade fever and severe pain. Parenteral crystalloids were also used to manage those who were unable to receive adequate oral fluids. Remarkably, no exclusion criteria were applied and all the affected patients recovered perfectly without any reported deaths caused by this outbreak (Figure 1).

Figure 1 Early immune-modulation using Kelleni’s protocol aborts dengue fever progression. NSAID: Non-steroidal anti-inflammatory drugs.

Furthermore, while co-infection of SARS-CoV-2 and dengue virus has been well documented[15], ibuprofen and other NSAIDs are currently recommended against to be used with DVD, according to a conditional recommendation that based on a very low to low certainty[2], mainly to avoid development of the potential thrombocytopenic hemorrhagic or gastritis complications[15]. Interestingly, a similar recommendation was initially globally adopted in the management of COVID-19 before later NSAIDs were proven safe and even lifesaving in SARS-CoV-2, RSV, influenza and Norwalk viral infections through real-life practice and clinical trials[6,13,14,16]. Early treatment using NSAIDs has been shown to possess the ability to halt the progression of these viral infection and prevent the occurrence of the complications in the vast majority of cases, if not all of them. Importantly, in-vitro studies of nitazoxanide and/or its active metabolite; tizoxanide have previously demonstrated the inhibition of intracellular replication of some flavivirdae including dengue virus serotype 2 through various mechanisms as well as the activation of immune-response genes to combat the infection[17-19]. Moreover, nitazoxanide has also been suggested to be effective against paramyxovirus infection including parainfluenza and human metapneumovirus[20]. Notably, azithromycin was adopted in Kelleni’s COVID-19 protocol mainly due to its immune-modulatory properties and it’s suggested to have the same lifesaving potential in dengue fever management as also evident in some case reports of dual SARS-CoV-2 and dengue virus infections.

Real-life insightful medical practice is the most important tool in combating pandemics

Importantly, we suggest that real-life insightful medical practice, not the potentially catastrophic theories as the one that initially led to avoiding NSAIDs in the management of COVID-19 nor the theoretical potentially biased meta-analysis studies as later demonstrated[13], has been a cornerstone in our battle against COVID-19[14]. Moreover, this real-life practice is most likely to play the same role in the times of future pandemics when there is no specific chemotherapy or treatment approach available. With DVD cases soaring globally, we recommend fellow physicians and colleagues especially in the heavily affected Latin American countries such as Peru, Brazil and Bolivia to immediately adopt nitazoxanide in the management of DVD, particularly as large dengue outbreaks are expected to occur every 3-4 years . This safe and economic broad spectrum antimicrobial, as an integral part of Kelleni’s immune-modulatory antiviral protocol, has been highly effective and lifesaving in our African management of several RNA viral infections such as SARS-CoV-2, RSV, Influenza and Norwalk in pediatric, geriatric and pregnant patients[6,13,14]. It is most likely, from my academic and clinical point of view, that dengue virus and Zika virus infection could be similarly managed especially in the high-risk groups in high-transmission regions, the same immune-modulatory principles as well as the highly favorable real-life outcomes justify for its prompt adoption. Moreover, Kelleni’s protocol could be considered ideal to manage DVD and COVID-19 co-morbidity, as well as dengue, chikungunya, and Zika dual or triple co-infections[3], and it continues to be effective in empiric management of those patients without prior requirements to perform expensive serological and/or molecular investigations and this approach is highly valuable economically[6,13].

However, until other reports or clinical trials can confirm my recommendation for the early use of ibuprofen/NSAIDs in the management of DVD, as has been done with COVID-19, it is vigilant to prescribe NSAIDs basing on a personalized basis. Patients presenting early in the course of infection or those presenting late but showing negative tourniquet test and/or living in well-resourced countries with an access to prompt medical care, should receive ibuprofen/NSAIDs to manage their DVD, as we strongly recommend. On the other hand, for those presenting relatively late or in circumstances where urgent medical intervention is lacking, such as in remote impoverished areas, it is vigilant to prescribe paracetamol together with nitazoxanide and azithromycin (modified Kelleni’s protocol), regardless of the results of tourniquet test. Moreover, well-designed sufficiently powered clinical trials should be conducted to fully assess and evaluate the safety of NSAIDs in early management of DVD as well as the efficacy of nitazoxanide with or without NSAIDs in its management as suggested in this report[21,22].

CONCLUSION

Taken together, we would like to suggest that early administration of Kelleni’s immune-modulatory antiviral protocol, which includes nitazoxanide and ibuprofen/NSAIDs, whether combined with azithromycin or not according the personalized medical assessment, can potentially abort the progression of the symptomatic DVD from the fever into the severe or critical hemorrhagic/shock phases in high risk groups of patients. This efficacy can be attributed to interfering with the overlapping immune-inflammatory pathways similarly involved in other viral infections. Therefore, Kelleni’s protocol using NSAIDs, nitazoxanide and/or azithromycin according to the clinical personalized evaluation, could potentially be the best empiric first line early management for SARS-CoV-2, dengue virus and other clinically experienced a yet to be explored respiratory and gastrointestinal tract viral infections. Furthermore, this broad-spectrum antiviral protocol can alleviate the burden on health care professionals and the health care authorities globally, particularly in developing countries. Kelleni’s protocol has the potential to eliminate the current requirement for expensive, resource-intensive and time-consuming serological, radiological, and molecular investigations and could be considered as a potentially broad spectrum antiviral holy grail (Figure 2).

Figure 2 Empiric use of Kelleni’s protocol to manage various viral infections. SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; NSAID: Non-steroidal anti-inflammatory drugs.