The protocol has been shown to be effective and safe for two pregnant patients and three children
Furthermore, the patients included 2 pregnant patients; one in her 9th week of gestation (confirmed by SARS CoV-2 rapid IgM test and later by Egyptian MOH PCR) and the other is a highly suspected case in her 18th week. They also have included 2 female children, 6 years and eight months- and 1.5-year-old sisters and a 4-year-old boy.
The pregnant patient who was confirmed by PCR has been also treated for rheumatoid arthritis and her COVID-19 clinical picture included fever, sore throat, fatigue and dry cough. We stopped both hydroxychloroquine and sulfasalazine already used for rheumatoid arthritis during the five-day treatment course to prevent potential adverse drug interactions and we successfully used azithromycin/nitazoxanide for her treatment. Similarly, NSAIDs were not prescribed for her as she was already on prednisone for her rheumatoid arthritis. Several prenatal four-dimensional ultrasonography that followed the treatment course showed a healthy female fetus with no suspected congenital abnormalities and on the 10th of December 2020, she delivered a full term healthy female offspring. The other pregnant was in her 18th week of gestation and was highly suspected, by history of close contact to a positive COVID-19 case, clinical manifestations of sore throat, cough and declining lymphocytic titer (24%) as compared to a previous CBC (39%) and  she completed one-week diclofenac potassium 50 mg b.i.d. course though she was strongly recommended to use it for only five days. However, she’s been totally relieved of COVID-19 symptoms with no significant adverse effects reported and she later delivered a full term healthy female offspring. We suggest that the potential benefits are exceeding the risks for this short-term NSAIDs regimen for pregnant patients before the third trimester, and we followed each case eagerly providing a personalized prescription. Similarly, we assessed any possible contraindication or potential drug-drug interactions.
Importantly, we prescribed the pediatric weight/age adjusted doses of nitazoxanide suspension, azithromycin suspension and ibuprofen syrup as illustrated. The mentioned three children were highly suspected by history of a close contact to a positive COVID-19 patient, clinical picture including fever, sore throat and/or cough. They recovered smoothly within the five-day regimen with no reports of adverse effects. Moreover, the elderly child complained of severe sore throat that led her to severe anorexia, while complaining of diarrhea and vomiting with a risk for dehydration while on paracetamol and she as well as her sister, complaining of milder manifestations, had completely recovered from their symptoms in three days but continued the five day full regimen and we suggest that the relief of the severe sore throat that restored the appetite might be due to the action of both ibuprofen and azithromycin. Notably, in other less documented suspected COVID-19 children, not mentioned in this manuscript, complaining of moderate cough episodes, we also prescribed the locally available antitussive suppositories/syrup containing oxomemazine, guaiphenesin, sodium benzoate and paracetamol once at night to allow a better sleep with no reported adverse effects.
A modified version of this protocol managed two complicated COVID-19 patients
Interestingly, a 48-year-old female patient complained of severe sore throat, malaise, fever and mild cough to which a family physician who is a tropical medicine consultant has asked for a CT chest that revealed patchy ground glass opacities scattered at right lung mainly peripheral in location associated with minimal thickening of the lung interstitium as well as peribronchial cuffing suggestive of COVID-19 (Figure 3), as described in the given report, and her family physician has prescribed paracetamol, betamethasone injection IM, doxycycline 100 mg for 15 days, azithromycin 500 mg orally, some vitamins and minerals as well as a syrup that contains antihistaminic and expectorant for three days. Her condition rapidly deteriorated with persistent fever, yellow vision, tachycardia and marked confusion. When we received a compassionate request from her husband and sons to help, we asked for an urgent CBC (Figure 4) that revealed a total leucocytic count of 5.1 X 103/µl with a low lymphocytic count of 12%. She was diagnosed positive for SARS CoV-2 IgM upon our request and we immediately stopped the bacteriostatic doxycycline, and ordered an immediate ketoprofen IM injection to be followed by diclofenac potassium b.i.d. and azithromycin 500 mg once daily for five days in combination with empiric parenteral cefoperazone; chosen for its readily availability in Egypt and its broad spectrum antibacterial efficacy against atypical respiratory micro-organisms that might be sharing in causing the high fever, 1 gm once daily for the first three days. Furthermore, we have added nitazoxanide 500 mg b.i.d. that also managed to control an episode of diarrhea that has been encountered after the start of treatment. We also stopped the previously prescribed antitussive syrup as explained earlier. Her condition improved gradually yet dramatically within five days and the CBC on the fifth day (figure 5) revealed an improved total leucocytic count of 6 X 103/µl with a significantly elevated lymphocytic count of 23%. She returned almost normal within two weeks complaining only of a mild cough and insignificant chest tightness that have disappeared later spontaneously.
Similarly, a 45-year-old male with clinical picture suggestive of mild-moderate COVID-19 including fever up to 39°C has received a protocol of azithromycin, paracetamol, zinc and vitamin C for only three days to which his body temperature fluctuated between 37°C and 38°C. However, a more severe clinical picture of high fever, sever fatigue, profuse sweating, severe episodes of cough with newly developed dyspnea has developed after two days of stopping treatment and we have received a request to treat on that fifth day. CT has confirmed a viral pneumonia with a bilateral scattered subpleural and parenchymal patches of ground glass opacities suggestive of COVID-19 for clinical and laboratory correlation (Figure 6) and we prescribed parenteral cefoperazone once daily for three days with another course of azithromycin 500 mg once daily for five days as well as oral diclofenac potassium t.d.s for the first two days followed by b.i.d. for three other days when his condition started to improve and we have not prescribed nitazoxanide for this patient waiting for the initial clinical response. The patient has experienced a significant clinical improvement as regards to most of his symptoms with return of body temperature to normal with no additional antipyretic or antibiotics after the new 5-day-course. He has also experienced gradual improvement of his severe cough and got free of its severe episodes after seven days with no antitussive prescribed as discussed before and returned almost normal as regards to cough, after 2 weeks. Interestingly, a follow up CT performed in another center one week after the first one has revealed regressive course of viral pneumonia with residual bilateral scattered patches of ground glass opacities according to its report (Figure 7). Moreover, though the lymphocytic count of this patient before treatment was 30% and not considered lymphopenic (Figure 8), it has increased to 47.9% (Figure 9) after the 5-day-course of treatment raising another possibility that it might have been deteriorating and the NSAIDs therapeutic intervention has efficiently stopped and reversed this deterioration as hypothesized before[10]. Notably, this patient C reactive protein level was 54 mg/l at the start of treatment and has been elevated to 90 mg/l at the end of the 5-day-course and one week after its end, the level has decreased to 9 mg/l. The initial increase in CRP might be explained by an undergoing concomitant bacterial infection that has been treated efficiently by the administered antibiotics. Furthermore, this patient was suffering from type 1 diabetes mellitus for 8 years and he has experienced a significant deterioration of his blood glucose profile to which we increased the total daily biphasic isophane insulin dosage with new addition of insulin glargine for two weeks. 
Notably, considering that the author was not in direct contact with those two patients; we have chosen a pharmacovigilant low dosed regimen of cefoperazone to avoid the very rare potential of vitamin K-dependent coagulopathy which might develop with serious diseases[23], and we administered cefoperazone with full 5-day-course of azithromycin. Interestingly, as the patients’ clinical condition improved, no increase of cefoperazone dose was required.
Pharmacoeconomics and pharmacovigilance influenced our study
We were waiting for the negative SARS CoV-2 (COVID-19) qualitative PCR test confirmation from the Egyptian expats living in KSA to develop a personal view for the best period of isolation but because of the large numbers of new infections, it was decided not to repeat the test after the clinical improvement and we agree with this pharmacoeconomically vigilant attitude. However, we recommended all the encountered Egyptian patients to remain isolated for 21 days from the beginning of the symptoms including at least one week, better ten days, of a totally symptom free period even if the PCR test revealed negative earlier and this recommendation was to avoid the possibility of any false negative results in Egypt. This advice was also based on a positive test from the nurse, although he was symptom free for more than 10 days to be fully elucidated by other research work to determine the best possible recommendation for the isolation period. We know that this advice for the isolation period of Egyptian patients is not consistent with the mainstream current guidelines, yet we chose to recommend more rest, if possible, especially as isolation rules are still changing[24] to be noted that a study has recommended a 22-day quarantine period to avoid the 6.7% failure who showed symptoms after the 14-day quarantine period; the 22-day quarantine showed a failure rate below 1% with 95% confidence[25].
A roadmap to combat COVID-19 using inexpensive available FDA-approved drugs
For adults, we used NSAIDs, either postprandial ibuprofen 400 mg (600 mg in KSA) b.i.d. or diclofenac potassium 50 mg b.i.d. alone for early cases complaining of sore throat, dry cough or mild dyspnea with no fever or fever less than 38°C and we believe they have helped to prevent the progression of COVID-19 especially for those patients who received them earlier. However, we recommend adding nitazoxanide, when available, to NSAIDs for patients complaining from diarrhea even if their temperature wasn’t above 38°C and it has also proved effective, as part of the whole protocol, to control a moderate diarrhea encountered in an adult patient whose temperature exceeded 38°C. Moreover, we prescribed the whole NSAIDs (as described)/nitazoxanide (500 mg bid)/azithromycin (500 mg once daily) five days protocol for COVID-19 adult patients complaining of fever more than 38°C. Importantly, other than their suggested potential curative COVID-19, we also noticed that NSAIDs had remarkably superior symptomatic clinical efficacy compared to paracetamol, for those who used paracetamol before switching to the new protocol, for controlling high fever, headache and malaise.
Notably, we allowed all patients to continue the already prescribed vitamin C, Vitamin D, zinc, lactoferrin or any other food supplements, although their proven clinical benefit, if any, are yet to be proved. We suggest these supplements when administered in their proper dosage are almost harmless regardless if they might or might not prove beneficial synergistic effect.
Confirmations and limitations
We would also like to declare that we believe that the drugs mentioned in this protocol are being used by other physicians in multiple parts of the world away from the clinical trials and sometimes without the scientific basis that explains their efficacy, this basis, we believe we have provided in our published manuscripts. We have been informed by an Egyptian colleague that he has used this preprinted protocol [26] effectively and safely to treat more than 15 COVID-19 patients and that he has also used another NSAIDs; celecoxib to manage pyrexia encountered in some of his patients with similar positive results. Notably, celecoxib, when even used as adjuvant therapy, has been shown to be beneficial for COVID-19 patients [27]. Similarly, a Mexican pulmonologist has sent a letter, after publishing the nitazoxanide/azithromycin protocol paper, confirming his successful practice managing 24 COVID-19 patients with nitazoxanide and complaining from a lack of protocol. A link to the full preprinted protocol has been sent to him. However, we had no funding to perform a formal clinical trial with double/quadrable blind randomization against a standard care protocol or to perform extensive and well organized investigations for each patient, many with limited economic resources, and these important limitations need to be addressed by other researchers with better capabilities to build on this protocol and release their results and/or modifications. Notably, we suggested adopting large randomized clinical trials, as described in two published manuscripts, for the drugs mentioned in this protocol and we also suggested other potential drugs [6, 9].
Conclusion
Finally, we wish to declare that the described short novel protocol, including NSAIDs as integral component, has shown a prompt efficacy, full compliance, tolerability and no reported serious adverse effects. Furthermore, we wish to suggest that this protocol might prove a battle changer/magic bullet one using inexpensive, safe and FDA approved drugs which are readily available all over the world in developing as well as developed countries and we suggest that our positive recommendation to use of NSAIDs as early as possible in the course of COVID-19 might be adopted soonest.
Ethics and consents
The author is a practicing member of the Egyptian syndicate of physicians since 2006. Every ethical command has been followed in all procedures mentioned in this manuscript.
Consents, verbal and later confirmed by written conversations through the mentioned social media applications, were obtained from each case/legal guardian involved in this study who have also authorized the release of their laboratory/radiological results.
Basing on an early knowledge represented later in published peer-reviewed articles; a moral obligation and a sacred oath to serve and help led to an immediate reply and thus getting consents from the mentioned Egyptian patients; most of them were residing in Egypt and the expat ones were either isolated or dwelled away from my province, was the only available method to conduct the current study. Notably, the author was working during most of this study in KSA and the preprint was published while he was working there. I have returned to Egypt after gratefully resigning from my Saudi University and return to my home country, university and patients on the 22nd of September 2020.
Availability of data and materials
The author declares full transparency and all data and materials related to this study are available. All the findings, other than the provided investigation reports which were written in English, were documented mostly in Arabic; the mother tongue of the patients as well as the author.
Conflict of interest
The author declares there’s no conflict of interest.
Funding/Financial exposure
None.
Acknowledgment
All the mentioned medical consultations were performed free of charge (Mat  10 :  8) and I pray that the Lord Almighty who guided my humble steps through the unimaginable hardships of publishing each of my COVID-19 articles, might use them for the glory of His holy name through saving precious lives; this is my foremost wish. The author would like to sincerely thank all the Egyptian patients who participated in this study as well as their family members who watched their treatment. Also, many thanks to Dr. Haroun Akhnoukh and Dr. Pablo Juárez for their precious feedback.
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