In a series of publications, we attempt to demonstrate the prophylactic role of bromhexine hydrochloride (BHH) and the curative role of high colchicine doses against COVID-19. Effects of long-term prophylaxis with BHH are present with two cases of elderly women with severe comorbidity. After long-term prophylactic use of BHH from 3 to 6 months, one did not fall sick from COVID-19 and the other passes it almost asymptomatically, even though all their family members fell ill.

The dramatic healing effect of colchicine was demonstrated in a family in which both spouses became ill with COVID-19 almost simultaneously. They are treated in different hospitals, and where colchicine is administered in high doses, the patient recovered. The other patient developed complications and died on standard treatment without high doses of colchicine.

An outpatient accidentally overdosed with colchicine (12.5mg). The therapy was stopped immediately. Clinically, on the third day, there are absolutely no symptoms. These cases re-affirm the prophylactic effect of BRH and the curative effect of high-dose colchicine.

COVID-19, bromhexine, colchicine, NLRP3 inflammasome

More than 4.5 years since the start of the coronavirus disease 2019 (COVID-19) pandemic, despite the enormous expenditure of financial and intellectual resources, an effective treatment has not been found.

The outpatient and hospital therapy proposed by the WHO is controversial, partially effective or downright harmful (Mitev 2023a; Morgenstern 2024; Sax 2024). For years, we have been trying to convince the scientific community that with the correct timing and dosage of bromhexine hydrochloride (BRH) and colchicine, the treatment problem is solvable (Mondeshki et al. 2022; Mondeshki et al. 2023; Mitev 2023a; Mitev 2023b; Mitev et al. 2023; Tiholov et al. 2024; Lilov et al. 2024; Mondeshki and Mitev 2024; Bulanov et al. 2024; Mitev 2024a).

We think that the effect of BRH is best when given continuously for prophylaxis during the next wave of COVID-19. BRH is also effective when given by inhalation for post-exposure prophylaxis, but when COVID-19 manifests itself clinically, the efficacy of BRH drops sharply because the virus is already in the cell (Mondeshki et al. 2022; Mitev 2023a; Mitev 2024a). Colchicine in high-doses has the remarkable effect in inhibiting the cytokine storm (CS) and preventing multi-organ damage and death (Mondeshki et al. 2022; Mitev et al. 2023; Mitev 2023a; Mitev 2023b; Mondeshki et al. 2023; Lilov et al. 2024; Mondeshki and Mitev 2024; Bulanov et al. 2024; Mitev 2024a; Tiholov et al. 2024). Colchicine is effective in outpatient and inpatient treatment, but only in high, but safe doses. We have demonstrated this in a series of publications (Mitev 2023a; Mitev 2023b; Mitev et al. 2023; Tiholov et al. 2024; Mitev 2024a) and dramatic clinical cases (Mondeshki et al. 2022; Mondeshki et al. 2023; Lilov et al. 2024; Mondeshki and Mitev 2024; Bulanov et al. 2024).

In this publication, we show two cases of adults with major co-morbidities receiving long-term prophylactic BRH; one family treated with colchicine, the other without and an ambulatory patient accidentally overdosed with colchicine, confirming our prophylactic and therapeutic regimen.

The first case was a 77-year-old vaccinated woman with multiple co-morbidities: chronic kidney disease with acute decline October 2021 associated with pyelonephritis – some recovery in kidney function, but not back to baseline; history of recurrent urinary tract infection; hypertension 30 years ago; pulmonary hypertension; Sjogren Larsson syndrome diagnosed 24 years ago; rheumatoid arthritis III–IV X-ray grade; Hashimoto’s thyroiditis; breast malignancy 2018 – previous surgery under regular follow-up at the breast clinic; peripheral vascular disease; anaemic syndrome; cataracts; uterovaginal prolapse with previous surgery; multiple orthopaedic surgery hip/shoulder ongoing. From October 2021, she took BRH prophylactically for 6 months (3×1 tablets per day). While staying in Bristol, UK with her daughter’s family, she fell ill with COVID-19 in March 2022, proven by an antigen test. The symptoms are only mild irritation of the throat and nose. Without any treatment, after one week the antigen test was negative. At the same time, her daughter and son-in-law (both vaccinated), who did not take BRH, became ill and had severe COVID-19.

The second case concerns an 88-year-old unvaccinated woman, with comorbid hypertension and type II diabetes. She took prophylactic BRH (3×1 tablets per day) for 4 months in 2021 and 3 months in 2022.

She has never been sick with COVID-19, despite direct contact with her family members who have contracted the disease (in September 2021).

The test done for Anti-SARS-CoV-2 IgG (ECLIA, Roche) on 01.12.2022 was 6.04 [BAU]/ml. It can only be assumed that after her family became ill, the woman developed anti-SARS-CoV-2 antibodies, which were detected 14 months later.

The presented case illustrates a family, consisting of a man and a woman, both infected with the SARS-CoV-2 virus, which led to complications of bilateral pneumonia in December 2020. The patients underwent treatment in two different healthcare facilities, each following distinct therapeutic regimens and resulting in varying clinical outcomes. Initially, both individuals exhibited symptoms of general fatigue and elevated temperature, with the man falling ill first, followed by his wife two days later.

Onset of the disease

The first patient is a 64-year-old man, weighing 93 kg, with co-morbidities that include type 2 diabetes, which is managed with oral therapy (Metformin 2000 mg/day) and demonstrates good glycaemic control, as evidenced by a last measured HbA1c of 6.4% taken ten days prior to the onset of symptoms. He also suffers from stage 2 arterial hypertension, treated with Nebivolol 5 mg/day and Amlodipine 10 mg/day. Notably, there is no history of underlying pulmonary diseases.

On the fifth day following the initial symptoms, he experienced a sudden deterioration, with oxygen saturation levels dropping to 91% and a persistent fever reaching 38 °C. He consulted his family doctor, who performed a rapid antigen test for SARS-CoV-2, which returned positive. A chest X-ray was conducted, revealing an enlarged cardiac silhouette along with bilateral infiltrative changes in both lung bases, but without any pleural effusions (Fig. 1). Consequently, he was evaluated for hospitalisation in a healthcare facility.

Figure 1. 

Radiographic data showing an enlarged cardiac shadow with bilateral investment changes in both lung bases without the presence of pleural effusions of first patient on the fifth day following the initial symptoms.

The therapy conducted in the hospital setting included the administration of Meropenem 3 times a day at 1.0 g intravenously, Metronidazole 2 times a day at 500 mg intravenously, Dexamethasone 2 times a day at 4 mg intravenously, Bromhexine 3 times a day at 4 mg orally and Nadroparin 0.4 ml per day subcutaneously. Oxygen therapy was provided at 4 litres per minute via a nasal mask.

During the 3-day stay in the therapeutic department, the patient experienced worsening respiratory failure with increased oxygen requirements and deteriorating inflammatory marker values from laboratory tests. The lack of clinical improvement and the worsening overall condition necessitated the continuation of treatment in the intensive care unit.

Oxygen needs continued to rise and the lack of effect from non- invasive ventilation therapy required the patient to be intubated and placed on invasive ventilation. The therapy included Meropenem 3 times a day at 1.0 g intravenously, Doxycycline 2 times a day at 100 mg intravenously, Nadroparin 2 times a day at 0.4 ml subcutaneously, Methylprednisolone 2 times a day at 60 mg intravenously and Bromhexine 2 times a day at 4 mg intravenously (Table 1).

Table 1.

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Laboratory results of first patient.

Marker	Unit	Min.	Max.	Day 1	Day 2	Day 5
4751-PCR test for COVID-19(SARS-CoV-2 RNA)	–	–	–	(+) positive	–	–
Leukocytes (Leu)	109/L	3.5	10.5	5.0	5.7	8.8
Erythrocytes (Er)	1012/L	4.4	5.9	4.8	4.7	5.1
Haemoglobin (Hb)	g/L	135	180	160	153	150
Haematocrit (Ht)	g/L	0.4	0.53	0.44	0.45	0.44
MCV	fL	82	96	91	87	88
MCH	pg	27	33	34	31	30
MCHC	g/L	300	360	366	356	345
Platelets (Tr)	109/L	130	440	180	160	141
NE % – Neutrophil granulocytes %	%	40	70	82.9	84.6	88.2
EO % – Eosinophilic granulocytes %	%	0	6.5	0	0.0	0.0
BA% – Basophilic granulocytes %	%	0	2	1	0	0
MO % – Monocytes %	%	1	11	5	6	6
LY % – Lymphocytes %	%	20	48	11	9	5.2
NE# – Neutrophil granulocytes-count	109/L	2	7	4.16	4.82	7.76
ЕО# – Eosinophilic granulocytes-count	109/L	0	0.5	0.1	0.0	0.0
BA# – Basophilic granulocytes-count	109/L	0	0.14	0.05	0	0.00
MO# – Monocytes-count	109/L	0	0.8	0.25	0.34	0.53
LY# – Lymphocytes-count	109/L	1	4	1.4	0.51	0.46
IG (%) – Immature granulocytes - %	%	0	5	0.1	0.4	0.6
IG # – Immature granulocytes - count	109/L	0	0.7	0.0	0.02	0.0
D-dimer	μg/L	0	0.55	1.2	2.1	3.1
Creatinine – serum	μmol/L	62	106	196	201	210
pH	–	7.35	7.45	7.4	7.45	7.3
pCO2	kPa	4.67	6	3.5	4.11	3.9
pO2	kPa	10	13	6.75	5.6	5.2
SB	mmol/L	21	25	20.5	23.7	28
BE (w)	mmol/L	-2.5	2.5	-3.3	4.1	5.1
O2 Sat	%	94	98	91	60	55
tCO2	mmol/L	20	27	19.5	21.5	25
CRP	mg/L	0	5	56	148.1	231
LDH	E/L	140	370	577	1893	2012
ESR	mm/h	0	20	92	–	–
ALAT	U/L	0	40	66	84	102
ASAT	U/L	0	40	56	68	83

Table 1 presents the laboratory results chronologically during the hospitalisation period. Laboratory results demonstrated rising levels of inflammatory markers and worsening respiratory failure. Along with this, there was an increase in the values of D-dimer, Creatinine, LDH, ALAT, ASAT, ESR, blood glucose, as well as a reduction of lymphocytes in absolute number and percentage. Neutrophil-type leukocytes progressively increase.

A follow-up chest X-ray was performed, showing bilateral involvement of both lung halves with extensive ground-glass opacities affecting two- thirds of the lung parenchyma bilaterally, without evidence of pleural effusions (Fig. 2). Laboratory results were presented chronologically during the hospitalisation period, demonstrating increasing values of inflammatory markers and worsening respiratory failure. Additionally, there was an increase in D-dimer and creatinine levels, along with a reduction in lymphocytes both in absolute numbers and percentage. Neutrophil-type leukocytes progressively increased.

Figure 2. 

Control X-ray examination and transaxial computed tomography of the chest (Chest CT) of the chest of first patient on day 5.

The patient died three days after being transferred to the intensive care unit.

The second patient was a 59-year-old woman weighing 60 kg, with no significant medical history. She visited her general practitioner accompanied by her husband and underwent a rapid antigen test for SARS-CoV-2, which returned positive. The patient showed asthenia, fatigue and a fever reaching up to 38 degrees Celsius. A chest X-ray (Fig. 3) revealed bilateral interstitial pneumonia, prompting the decision for hospitalisation.

Figure 3. 

An X-ray of second patient upon admission.

She was admitted to a different healthcare facility from her husband. The initiated treatment plan included:

Colchicine: 0.5 mg tablets – 3 tablets three times on the first day (0.075 mg/kg), then 1 tablet three times daily thereafter; Doxycycline: 200 mg IV twice daily; Methylprednisolone: 40 mg IV three times daily for the first three days, followed by 40 mg twice daily for two days and then 40 mg IV daily for the next two days; Bromhexine: Inhalation of 4 mg in 1 ampoule three times daily, mixed with 2 ml of saline for the duration of her hospitalisation; Nadroparin: 0.4 ml subcutaneously twice daily; Quamatel: 40 mg orally twice daily throughout her hospital stay.

Upon admission, the patient exhibited respiratory failure, which was addressed with oxygen therapy at 3 l/min via nasal cannula, maintaining an average oxygen saturation of 91%–93%. By the second day of hospitalisation, the patient became afebrile, experiencing a significant reduction in subjective complaints of fatigue during routine physical activities, with no reports of dyspnea.

Laboratory tests performed during the treatment period, illustrated in Table 2, showed a decrease in inflammatory markers and lower levels of D-dimer. A follow-up chest X-ray taken on the seventh day of treatment, shown in Fig. 4, indicated signs of improvement in the radiological findings. Based on these results, the patient was assessed as appropriate for discharge.

Table 2.

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Laboratory results of second patient.

Marker	Unit	Min.	Max.	Day 1	Day 4	Day 8
4751-PCR тест за COVID-19 (SARS-CoV-2 RNA)	–	–	–	(+) positive	–	(-) negative
Leukocytes (Leu)	109/L	3.5	10.5	7.8	8.1	9.2
Erythrocytes (Er)	10^12/L	4.4	5.9	4.8	4.9	4.7
Haemoglobin (Hb)	g/L	135	180	123	121	120
Haematocrit (Ht)	g/L	0.4	0.53	0.39	0.41	0.4
MCV	fL	82	96	81	82	85
MCH	pg	27	33	26	28	27
MCHC	g/L	300	360	315	324	315
Platelets (Tr)	109/L	130	440	316	340	354
NE % – Neutrophil granulocytes %	%	40	70	78.4	74.9	62
EO % – Eosinophilic granulocytes %	%	0	6.5	2.1	0.0	0.0
BA% – Basophilic granulocytes %	%	0	2	1	0	0
MO % – Monocytes %	%	1	11	7.1	8	10.5
LY % – Lymphocytes %	%	20	48	11	15.9	26
NE# – Neutrophil granulocytes – count	109/L	2	7	6.12	6	5.7
ЕО# – Eosinophilic granulocytes – count	109/L	0	0.5	0.16	0.0	0.0
BA# – Basophilic granulocytes – count	109/L	0	0.14	0.08	0.01	0.00
MO# – Monocytes – count	109/L	0	0.8	0.55	0.65	0.96
LY# – Lymphocytes – count	109/L	1	4	0.86	1.28	2.39
IG (%) – Immature granulocytes – %	%	0	5	0.4	1.2	1.5
IG # – Immature granulocytes – count	109/L	0	0.7	0.0	0.1	0.14
D-dimer	μg/L	0	0.55	1.5	1.1	0.85
Creatinine – serum	μmol/L	62	106	89	95	82
pH	–	7.35	7.45	7.4	7.41	7.39
pCO2	kPa	4.67	6	4.1	4.5	4.5
pO2	kPa	10	13	7.8	8.1	8.4
SB	mmol/L	21	25	20.5	24	25
BE (w)	mmol/L	-2.5	2.5	2.8	2.5	2.3
O2 Sat	%	94	98	91	92	94
tCO2	mmol/L	20	27	23	25	24
CRP	mg/L	0	5	22	15	9
LDH	E/L	140	370	572	511	480
ESR	mm/h	0	20	40	–	22
ALAT	U/L	0	40	45	41	42
ASAT	U/L	0	40	35	32	38
blood glucose	mmol/L	3.9	5.6	5.5	6.5	5.4

Figure 4. 

Shows the control radiograph taken on the 7^th day after the start of treatment of second patient, upon discharge from the hospital. Demonstrates the reverse development of the X-ray morphological changes, without the presence of pleural effusions.

Table 2 demonstrates a reduction in inflammatory markers over the treatment period. Neutrophil leukocytes reach normal values, lymphocytes increased in number and percentage reaching normal. D- dimer values from pathologically elevated values showed a tendency towards normalisation during the course of treatment. The values of oxygen saturation improved, reaching the norm without oxygen substitution. CRP values reached normal.

The two cases demonstrate the progression of disease due to SARS- CoV-2 viral pneumonia, with both patients showing a similar onset of initial symptoms. Neither patient had a history of pulmonary disease or had been on medications related to previous respiratory issues. Two distinct therapeutic regimens were implemented (with or without colchicine), leading to different therapeutic outcomes.

A 55 kg 42-year-old unvaccinated woman was admitted with complaints of persistent fever up to 39 °C, general fatigue, dry cough, muscle and joint pain. She was diagnosed with COVID-19 with an antigen test. At the time of the illness (September 2021), the dominant variant of SARS- CoV-2 in Bulgaria was Delta. The woman was prescribed to take 5 tablets of colchicine on the first day. In addition, bromhexine 4 × 2 tablets was prescribed, doxycycline (2 × 1), antithrombotic therapy with clopidogrel, aulin (2 × 1) and nexium. Due to a misunderstanding, the patient took 5 tablets 5 times on the first day (12.5 mg or 0.23 mg/kg). On the second day, until the attending physician was called, she took another 3–4 tablets. The woman had diarrhoea, more than five bowel movements. Colchicine was stopped immediately, as was any other therapy.

Clinically, on the third day, there were absolutely no symptoms. She just felt a little tired. No diarrhoea.

On the 10^th day, an X-ray was taken. The lung was clean. From the laboratory tests: ESR-22 mm/h [1–20]; CRP-12 mg/l [0–5]; Leukocytes – 8.9 × 109/l [3.5–10.5]; Ne% – Neutrophilic granulocytes – 76 [40–70]; D-dimer-0.6 mg/l [0–0.55]; Alanine aminotransferase (ALAT)-34 U/l [0–41]; Aspartate aminotransferase (ASAT)- 38 U/l [0–40]; creatinine- 76 µmol/l [53–97.2]. Antigen test was negative.

Our strategy to combat COVID-19 is to block Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from entering the cell and to inhibit the hyperactivated nucleotide-binding oligomerisation domain- like receptor containing pyrin domain 3 (NLRP3) inflammasome which is a central mediator of severe COVID-19 causing the CS, with subsequent multi-organ damage and death (Mitev 2023a; Mitev 2024a). The principal SARS-CoV-2 cell entry (via plasma membrane) is related with the cell-surface transmembrane protease serine subtype 2 (TMPRSS2) which cleaves the spike protein leading to the fusion of the viral and host membranes (Hoffmann et al. 2020). BRH has a selective inhibitory effect on TMPRSS2, thus inhibiting the SARSCoV-2 entry into the cell (Lucas et al. 2014; Hoffmann et al. 2020; Depfenhart et al. 2020). BRH is most effective when taken prophylactically (Fig. 5), because it blocks in advance the entrance of the SARS-CoV-2 to the cell (Mitev 2023a). Our two cases of elderly women with severe co-morbidity who took BRH tablets prophylactically for 3 to 6 months demonstrate just that. However, in the cases of post-exposure prophylaxis and manifestation of COVID-19, the time and method of administration (inhalations) are the leading factors for the successful action of BRH (Mitev 2023a). Positive results for the effect of BRH in post-exposure prophylaxis were reported (Tolouian et al. 2022; Mikhaylovet al. 2022). Prevention of COVID-19 with cheap BRH can reduce illnesses, if any, they are mild, hospital admissions are reduced, the pandemic is contained and millions of lives can be saved (Mitev et al. 2024).

Figure 5. 

Time and dose dependence for effective treatment of COVID-19 with BRH and colchicine.

The NLRP3 inflammasome plays a central role in the complications of COVID-19 (Freeman and Swartz 2020). If we want to save the severely ill COVID-19 patient, the hyperactivated NLRP3 inflammasome must be inhibited. Colchicine has the remarkable property of accumulating in white blood cells, where life-threatening CS develops (Leung et al. 2015). Increasing doses of colchicine in these cells achieved the micromolar concentrations required to inhibit the NLRP3 inflammasome (Mitev 2023a; Mitev 2024a). High doses of colchicine may be particularly helpful in treatment of COVID-19 obese or diabetic patients with higher metaflammation and NLRP3 activation (Rabbani et al. 2024). Our results strongly support this view (Lilov et al. 2024; Mondeshki and Mitev 2024; Mitev 2024b).

The case of the family, affected almost simultaneously by COVID-19, is an eloquent and tragic example of the life-saving effect of high doses of colchicine. It should be strongly emphasised that the colchicine doses we use have been used in the past and are completely safe (Mitev 2023a; Mitev 2023b; Tiholov et al. 2024; Mitev 2024a).

Not long ago, we described an inpatient with COVID-19 pneumonia and pericardial effusion who mistakenly took 15 mg of colchicine over 10 hours. Remarkably, this single overdose of colchicine, without any additional therapy, resulted in the complete recovery of bilateral pneumonia and pericardial effusion (Mondeshki et al. 2023). Two other outpatients took

12.5 mg/24 h and their symptoms resolved within three days. In all three patients, a lower dyspeptic syndrome was observed, controlled with symptomatic medicines for 24 hours (Mondeshki et al. 2023). The case described by us is the fourth one with an accidentally taken overdose of colchicine 12.5mg [0.23mg/kg]. Clinically, on the third day, there were absolutely no symptoms.

We do not recommend such doses, but these cases raise the question of whether, in particularly severe COVID-19, the maximum dose we give (0.045 mg/kg) should be increased to 0.1 mg/kg, which is below the threshold of intoxication (Mitev 2023b; Mitev 2024a).

The effectiveness of BRH is highly dependent on the timing of administration (Fig. 5). It is most effective when given prophylactically, for more than 1 month. It can be very effective when taken immediately by inhalation for post-exposure prophylaxis. By the time symptoms are present, the virus has already entered the cell, but BRH can limit its spread. As an 3Clpro/Mpro protease inhibitor, it could inhibit SARS-CoV-2 replication. Its active demethylated metabolite, ambroxol, is a potent inducer of surfactant synthesis. In addition, BRH can support the healing process as cough suppressant, expectorant, mucolytic and anti-inflammatory agent, thus reducing swelling and irritation in the respiratory tract. The timing of colchicine administration is also important, but the dose is decisive. Only high doses of colchicine could inhibit the NLRP3 inflammasome and prevent CS.

Conflict of interest

The authors have declared that no competing interests exist.

Ethical statements

The authors declared that no clinical trials were used in the present study.

The authors declared that no experiments on humans or human tissues were performed for the present study.

Informed consent from the humans, donors or donors’ representatives: Medical control commission of umbal “Aleksandrovska” EAD Protocol No. LKK-17-3-54-2020.

The authors declared that no experiments on animals were performed for the present study.

The authors declared that no commercially available immortalised human and animal cell lines were used in the present study.

Funding

This study is financed by the European Union-NextGenerationEU, through the National Recovery and Resilience Plan of the Republic of Bulgaria, project № BG-RRP-2.004-0004-C01.

Author contributions

All authors have contributed equally.

Author ORCIDs

Tsanko Mondeshki https://orcid.org/0000-0002-2511-7016

Hristo Georgiev https://orcid.org/0000-0001-9828-1610

Violeta S. Dimitrova https://orcid.org/0009-0006-8649-2051

Vanyo Mitev https://orcid.org/0000-0001-7528-590X

Data availability

All of the data that support the findings of this study are available in the main text.