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Severe Spinal Column Deformity from Scoliosis with Harrington Rods Implant

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DOI: 10.31038/AWHC.2020344

 

Severe scoliotic deformity of the thoracolumbar spine imposes a significant anesthesia challenge for non-spine surgery. Patients with severe scoliosis are at increased risk for perioperative morbidity and mortality due to underlying pulmonary and cardiac dysfunctions [1-3]. Stress, pain, mechanical ventilation, and surgery-induced inflammation can further increase the risk of postoperative cardiopulmonary failure. We present a preoperative chest radiograph demonstrating extensive thoracolumbar scoliosis with Harrington rods implant, anatomic distortion, and bony dysmorphism (Panel A, white arrow). The patient underwent a living donor kidney transplant under general anesthesia. Preoperative anesthesia and surgical planning is crucial and should focus on airway difficulty, ventilation management, positioning, new kidney location, and postoperative pain management.

The kidney transplant is a heterotopic transplant surgery meaning the kidney is placed in a different location than existing kidneys. The new kidney is on the right or left side of the abdomen to allow the donor kidney to be easily anastomosed surgically to blood vessels and the bladder of the recipient. Due to the extensive deformity of the spinal column and right chest wall (Panel B, black arrow), the operation was performed in the left lateral decubitus position. Moreover, the donor kidney was placed to the right iliac fossa to decrease the risk of left lung atelectasis, restricted breathing, and sprinting from pain.

Ultrasound-guided quadratus lumborum was difficult in this patient due to atrophy of trunk muscles, chronic scarring, and artifacts from the implant, which required careful assessment of anatomical landmarks to perform a successful nerve block.

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References

  1. APA Bradford, David S, Tay B, Hu S (1999) Adult Scoliosis: Surgical Indications, Operative Management, Complications, and Outcomes. Spine24: 2617-2629. [crossref]
  2. Albert TJ, Purtill J, Mesa J, McIntosh T, Balderston RA (1995) Health outcome assessment before and after adult deformity surgery. A prospective study. Spine 20: 2002-2005. [crossref]
  3. Kulkarni Anand H, Ambareesha M (2007) Scoliosis and anaesthetic considerations. Indian Journal of Anaesthesia. 51: 486-495

Treatment of Vaginal Atrophy with the Aqueous Extract of Triticum vulgare: Comparison between Different Pharmaceutical Forms

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DOI: 10.31038/AWHC.2020335

Abstract

Decreased estrogenization in post-menopausal women causes changes in the lower urinary tract. Vulvovaginal atrophy (VVA) is a pathological condition resulting from those changes. VVA has a negative effect on the quality of life therefore prompting a search for well tolerated therapeutic options. This article was aimed to evaluate whether the participation of the patient in the choice of the therapy may improve the adherence to the treatment. In particular, there are two distinct pharmaceutical forms in vaginal cream and pessaries based on the Triticum vulgare extract (TVE) for the treatment of post-menopausal VVA.  We examined the clinical reports of48 women with VVA who chose to be treated with Fitostimoline® 20% vaginal cream (based on TVE, 2-phenoxyethanol; glycerine; white vaseline; sodium cetyl stearyl sulfate; cetyl stearyl alcohol; decyl oiled; methyl parahydroxybenzoate; propyl parahydroxybenzoate; purified water. Produced by Farmaceutici Damor, Naples, Italy) and 43 who preferred Fitostimoline®600 mg pessaries (based on TVE,2-phenoxyethanol; macrogol 400; macrogol 1500; macrogol 12000.Produced by Farmaceutici Damor, Naples, Italy) for a 3-monthtreatment. Signs and symptoms of VVA were available during the baseline and after 12 and 90-day treatment visits.

Adhering to the patient’s choice allowed for a very high compliance to the prescribed therapy in the whole study population, and we recorded a significant reduction of the total symptom score (TSS) inboth women treated with the vaginal cream and in those who underwent pessary therapy, without any differencein TTS and in its single components between thetwo pharmaceutical formulation groups.

Thus, the availability of two distinct formulations of Fitostimoline® pessaries and vaginal cream seems to be particularly useful for the treatment of VVA.

Keywords

Vulvovaginal atrophy, Fitostimoline® pessaries, Fitostimoline® vaginal cream

Introduction

Vulvovaginal atrophy (VVA) is a common condition associated with decreased estrogenization of the vaginal tissue. It can occur at any time in a woman’s life cycle, but it is more frequent in the postmenopausal phase, since it affects around 90% of postmenopausal women [1]. Other than menopause, VVA may appear during hypoestrogenic conditions, such as lactation, various breast cancer treatments, and use of certain medications. In these cases, VVA may resolve spontaneously when estrogen levels are restored [2]. VVA symptoms are all dependent from decreased estrogenization and include: Dryness, soreness, irritation and dyspareunia with increased urinary frequency, urgency, and urge incontinence [3]. Clinical findings include the presence of pale and dry vulvovaginal mucosa with petechiae. Vaginal rugae disappear, and the cervix may become flush with the vaginal wall. A vaginal pH of 4.6 or more supports the diagnosis of VVA because the low level of estrogen may decrease the number of lactobacilli thus causing increased pH of the vagina [4].

Only a quarter of women with VVA seek for treatment [5]. The

first- line treatment of VVA is a continuous sexual relationship, using non-hormonal lubricant over the counter vaginal [6]. The systemic and local estrogen administration is recommended for the treatment of VVA in postmenopausal women [7]. Although hormone therapy may alleviate the short and long term complications of menopause, such as hot flashes, night sweats, and VVA, it may increase the risk of breast and endometrial cancer [8]. Because of the adverse effects of estrogen therapy, some women prefer not to use this method for alleviating VVA, and they tend to use non-hormonal medication for this matter[9]. In this regard, it is noteworthy the evidence that a local treatment based on hyaluronic acid is more effective than hormonal therapy in improving VVA symptoms [10]. More recently, it has been showed that the aqueous extract of Triticum vulgare (TVE) in cream [11] and pessaries [12] formulation could reduce sign and symptoms of VVA in postmenopausal women. TVE containing mainly poly/ oligosaccharides’ components has been extensively used in different pharmaceutical forms. The Damor Farmaceutici TVE, because of its global patent based on its production process, has unique characteristics that lead to its application in VVA treatment. In fact, as recently demonstrated, Damor TVE has a regenerating [13,14], antinflammatory [15] and anti-MMP9 activity [16], and antioxidant activity [17], which play a crucial role in the treatment of VVA. Furthermore, these recent studies suggest that Damor TVE is at least as efficacious as hyaluronic acid in favoring tissue re-epithelization and in contrasting inflammation. For this reason, Damor TVE cream and pessaries formulations (Fitostimoline® vaginal cream and pessaries) are used in the gynecological clinical practice as an alternative to hyaluronic acid in the treatment of VVA.

Since in a long-term treatment it may be useful to involve the patient in the choice of the pharmaceutical formulation to use, in order to improve adherence to the treatment, the availability of two different pharmaceutical formulations based on Damor TVE, may be particularly useful to improve the adherence to the treatment. Thus, we used a large population of women with VVA treated with the vaginal cream or the pessaries of Damor TVE, according to their preference, to evaluate in real word clinical practice whether this “therapeutic agreement” may improve the compliance in a long-term treatment.

Patients and Treatments

In an Outpatient Gynecological Clinic database we selected 91 women, aging between 18 and 70 years, with evidence of VVA (physiological, pharmacologically induced or surgery-dependent) who had symptoms and objective signs of vaginal atrophy plus amenorrhea for at least 12 months, who chose to receive one of following treatments for a 3 months’ period:

• Fitostimoline 20% vaginal cream (based on TVE, 2-phenoxyethanol; glycerine; white vaseline; sodium cetyl stearyl sulfate; cetyl stearyl alcohol; decyl oiled; methyl parahydroxybenzoate; propyl parahydroxybenzoate; purified water. Produced by Farmaceutici Damor, Naples, Italy).

• Fitostimoline 600 mg pessaries (based on TVE, 2-phenoxyethanol; macrogol 400; macrogol 1500; macrogol 12000. Produced by Farmaceutici Damor, Naples, Italy).

The treatments were locally applied every evening for 3 months. Patients were asked to avoid vaginal sexual intercourse during the entire study period.

We excluded women with other gynecological diseases (in addition to VVA), like the presence of metabolic or endocrine diseases (e.g. uncontrolled diabetes mellitus) or of other local/systemic diseases that could potentially interfere with the study parameters (concomitant treatment with antibiotics/antiseptic agents, steroidal and non-steroidal anti-inflammatory drugs, analgesics (except paracetamol as pain killer)). All patients gave their informed written consent to the use of their clinical data for scientific purposes.

Outcome Measures

Signs and symptoms of VVA were available during the baseline visit and after 12 and 90 days of treatment. Six subjective symptoms (burning, pain, itching, vaginal dryness, dyspareunia and dysuria) and 5 objective signs (mucous dryness, pale mucosa, thin vaginal folds, mucous fragility, petechiae) of vaginal atrophy were evaluated by a semi-quantitative scale (0 = absence of the sign/symptom; 1 = mild sign/symptom; 2 = moderate sign/symptom; 3 = severe sign/ symptom) expressed for both single signs and symptoms and for their sum (total symptoms score, TSS). Adverse events occurrence and vital signs (blood pressure, heart rate, body temperature) were reported as safety parameters. At the end of the treatment period, a satisfaction opinion was expressed by the patient in terms of excellent, good, to be improved, negative. For the statistical analysis, post hoc simultaneous multiple comparisons were done by Bonferroni’s analysis.

Results

Out of 91 women recruited, 48 were treated with Damor TVE vaginal cream and 43 with the pessaries. The two groups of women were comparable by demographics and clinical characteristics (Table 1). The menopause origin for the majority of women was physiological (Table 2). Only a few women had a pharmacological or surgical menopause (Table 2). However, the origins of the menopause were comparable between the two groups of women. All the patients were completely adherent to the treatment since all completed the 90-day treatment period with a compliance, percentage of the prescribed therapy assumed, above 95%: 98% for Fitostimoline® vaginal cream and 95% for Fitostimoline® pessaries (Figure 1).

Table 1: Patient demographic characteristics.

Pessaries
(N = 34)

Cream
(N = 38)

p Value

Age (years)

51.4 ± 11.0

53.2 ± 10.3

NS

Menopause (months)

32.0 ± 34.5

37.5 ± 31.7

NS

Table 2: Menopause origin.

Pessaries
(N = 34)

Cream
(N = 38)

p Value

Physiological (%)

93.1

89.6

NS

Surgical (%)

4.7

6.3

NS

Pharmacological (%)

2.2

4.1

NS

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Figure 1. Patients adherence to the treatment with Fitostimoline® vaginal cream and Fitostimoline® pessaries.

By evaluating together patients treated with the vaginal cream and the pessaries, a significant reduction of the TSS was detected both at visit 2 and at visit 3 (Figure 2). When the TSS score was evaluated separately for women treated with Fitostimoline® vaginal cream and those treated with Fitostimoline® pessaries no significant difference in the TSS was detected between the treatment groups (Figure 3). As shown in Figure 3, a significant reduction in the TSS occurred from visit 1 to visit 2 in the two study groups (TSS = 20,1 at visit 1 and 14,4 at visit 2 to for Fitostimoline® pessaries; TSS = 19,1 at visit 1 and 10,9 at visit 2 for Fitostimoline® vaginal cream). A further significant reduction of the TSS score was observed from visit 2 to visit 3 either in patients treated with the vaginal cream (TSS = 10,9 at visit 2 and 5,7 at visit 3) than in those treated with the pessaries (TSS = 14,4 at visit 2 and 8,8 at visit 3) (Figure 3).

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Figure 2. TSS evaluation for treatment with both Fitostimoline® pessaries and Fitostimoline® vaginal cream.

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Figure 3. TSS variation in patients treated with Fitostimoline® pessaries and Fitostimoline® vaginal cream.

Also the single components of the TSS score of VVA were evaluated for both groups of women (Figures 4 and 5). A significant reduction of the main VVA symptoms of pain, burn, itching, dryness, dyspareunia, dysuria, petechiae was observed both in patients treated with the vaginal cream and those receiving the pessaries at visit 2 and visit 3 versus the basal visit (Figures 4 and 5). Furthermore, a statistically significant progressive improvement of all these symptoms evaluated was observed from visit 2 to visit 3 (Figures 4 and 5) without any difference between the groups of treatment (Figures 4 and 5).

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Figure 4. Symptoms variation after treatment with Fitostimoline® pessaries.

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Figure 5. Symptoms variation after treatment with Fitostimoline® vaginal cream.

Finally, in order to assess whether the women were satisfied by the chosen treatment, vaginal cream or the pessaries, the patient’s satisfaction was evaluated. As indicated by Figure 6, 65,1% of women treated with Fitostimoline® pessaries and 68,8% of women treated with Fitostimoline® vaginal cream reported an “excellent satisfaction”, 32,6% and 31,2%, respectively had a “good satisfaction”, while only 2.3% of women treated with Fitostimoline® pessaries referred a “negative satisfaction’’.

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Figure 6. Evaluation of the satisfaction to the treatment with Fitostimoline® pessaries and vaginal cream.

Discussion

The transition from evidence medicine, “one size fits for all”, to precision medicine, “tailored treatment”, requires not only the demonstration of the efficacy and tolerability of a given treatment obtained in randomized trials but also its detailed characterization which can be obtained exclusively in daily clinical practice using large groups of patients. Furthermore, in order to solve the problem of the low adherence and compliance to the prescribed therapy observed in all the long-term treatments, it has been suggested that the patient should be adequately informed and involved in the choice of the therapy.

Thus, the availability of large database of Outpatient Clinics seems particularly useful to satisfy these needs for very common diseases which require long-term treatments. In order to verify this assumption for VVA we obtained from the data base of an Outpatient Gynecological Clinic the clinical records of 91 women with VVA who had been involved in the choice of the treatment and had undergone a 90-day therapy with Fitostimoline® vaginal cream or with Fitostimoline® pessaries. The results of the present study confirm that the involvement of the patients in the choice of the treatment markedly improves the adherence and the compliance to the therapy prescription since at our knowledge there are no reports in the real world clinical practice describing a 100% adherence in a 3 month treatment with the assumption of more than 95% of the drug prescribed.

Our results do not allow any speculation of the efficacy of TVE pharmacological formulations in the treatment of VVA since we have no comparison with placebo or active drug. However, experimental studies suggest that there is a rationale for the use of TVE for the treatment of VVA [13-16] and evidence of their efficacy in the treatment of VVA obtained in clinical studies are available in the literature [11,12]. An indirect support to these data seems to be corroborated by the comparison between the percentage of success achieved in our population, as expressed by the reduction in TSS score, and that reported with the use of hyaluronic acid in the treatment of VVA (Figure 2) [10].

Furthermore, the observation that there are no differences between TVE pessaries and vaginal cream either in the evaluation of the TSS or in the evaluation of the single symptoms, support the possibility to allow a personal choice between the two pharmacological formulations. Finally, the time course of the therapeutic effect that appears to consolidate over time seems to suggest that the mechanism of action of the Fitostimoline® formulations is actually pathogenic rather than symptomatic. The limitations of this study are that this is not a clinical trial but an observational study on a wide range of cases. For this reason, we do not have a validation of efficacy which however already exists for this products and it was not in the objective of the study which consisted in assessing whether the availability of different pharmaceutical forms by favoring the “therapeutic concordance” can be useful in improving compliance.

Conclusion

For the purposes of therapeutic agreements between physicians and patients, which is the mechanism currently suggested to improve adherence to therapy, the availability of different pharmaceutical forms represents an issue of great relevance. In order to manage the choice by the physician, however, it is essential to have full knowledge of the potential of the different pharmaceutical forms. For this reason, we can conclude that the two distinct formulations of TVE, pessaries and vaginal cream, didn’t show any significant difference in the treatment of the VVA, both in terms of efficacy and of compliance, and could be alternatively used for the treatment of VVA.

References

  1. Palacios S, Nappi RE, Bruyniks N, Particco M, Panay N (2018) The European Vulvovaginal Epidemiological Survey (EVES): Prevalence, symptoms and impact of vulvovaginal atrophy of menopause. Climacteric 21: 286-291. [crossref]
  2. Mac Bride MB, Rhodes DJ, Shuster LT (2010) Vulvovaginal atrophy. Mayo Clin Proc 85: 87-94. [crossref]
  3. Castelo-Branco C, Cancelo MJ (2008) Compounds for the treatment of atropic vaginitis. Expert Opin Ther Pat 18: 1385-1394.
  4. Sturdee DW, Panay N (2010) Recommendations for the management of postmenopausal vaginal atrophy. Climacteric 13: 509-522. [crossref]
  5. Castelo-Branco C, Rostro F (2007) Treatment of atrophic vaginitis. Therapy 4: 349- 353.
  6. Noumova I, Castelo-Branco C (2018) Current treatment options for postmenopausal vaginal atrophy. Int J Women’s Health 10: 387-395 [crossref]
  7. North American Menopause Society (2007) The role of local vaginal estrogen for treatment of vaginal atrophy in postmenopausal women: 2007 position statement of the North American Menopause Society. Menopause 14: 355-369. [crossref]
  8. Wentzensen N, Trabert B (2015) Hormone therapy: Short-term relief, long-term consequences. Lancet 385.
  9. Ibe C, Simon JA (2010) Vulvovaginal atrophy: Current and future therapies. J Sex Med 7: 1042-1050. [crossref]
  10. Jokar A, Davari T, Asadi N, Ahmadi F, Foruhari S (2016) Comparison of the hyaluronic acid vaginal cream and conjugated estrogen used in treatment of vaginal atrophy of menopause women: a randomized controlled clinical trial. Int J Community Based Nurs Midwifery 4: 69-78. [crossref]
  11. Mollica G, Bonaccorsi G, Martinello R (2008) Evaluation of efficacy and tolerability of Fitostimoline vaginal cream (Damor Farmaceutici) in the treatment of vaginal inflammation and vulvar dystrophy: A double-blind randomized controlled trial Gazzetta Medica Italiana Archivio per le Scienze Mediche 167: 87-95.
  12. Mollica G, Bonaccorsi G, Martinello R (2008) Valutazione di efficacia e tollerabilità di Fitostimoline Ovuli Vaginali (Damor Farmaceutici) nel trattamento delle affezioni flogistico-distrofiche della vagina. Studio controllato in doppio cieco. Gazzetta Medica Italiana Archivio per le Scienze Mediche 167: 97-103
  13. Sanguigno L, Minale M, Vannini E, Arato G, Riccio R, et al. (2015) Oligosaccharidic fractions derived from Triticum vulgare extract accelerate tissue repairing processes in in vitro and in vivo models of skin lesions. J Ethnopharmacol 159: 198-208. [crossref]
  14. D’Agostino A, Pirozzi AVA, Finamore R, Grieco F, Minale M, et al. (2020) Molecular mechanisms at the basis of pharmaceutical grade triticum vulgare extract efficacy in prompting keratinocytes healing. Molecules 25: 431. [crossref]
  15. Sanguigno L, Casamassa A, Funel N, Minale M, Riccio R, et al. (2018)Triticum vulgare extract exerts an anti-inflammatory action in two in vitro models of inflammation in microglial cells. PLoS One. 13: 197493. [crossref]
  16. Funel N, Dini V, Janowska A, Loggini V, Minale M, et al. (2020) Triticum vulgare extract modulates protein-kinase b and matrix metalloproteinases 9 protein expression in bv-2 cells: Bioactivity on inflammatory pathway associated with molecular mechanism wound healing. Mediators of Inflammation 1-13.
  17. Antonucci I, Fiorentino G, Contursi P, Minale M, Riccio R, et al. (2018)Antioxidant capacity of rigenase®, a specific aqueous extract of triticum vulgare. Antioxidants (Basel) 7: 67. [crossref]

The Effect of COVID-19 Pandemic on Urolithiasis Management and Urologists in the Gulf Countries: A Survey of Urologists in GCC

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DOI: 10.31038/IJNUS.2020211

Abstract

Objective: To explore the effects of COVID-19 on urolithiasis management and on the medical practice of urologists in Gulf countries.

Methods: A web-based survey was sent to urologists in the six countries in the Gulf Cooperation Council (GCC). The survey consisted of 23 questions about their working environment, urolithiasis management experience, and the policies of their facilities during the COVID-19 pandemic.

Results: During the one-week survey period, responses were received from 191 urologists working in the six GCC countries. Responses were received from urologists in all six countries but the numbers differed markedly. Of the 191 urologists who responded, 160 (83.8%) were experienced urologists and 31 (16.2%) were urology residents. Eighty-four (44.0%) volunteered for COVID-19 management rather than urology, 22 (11.5%) were infected with COVID-19 and 38 (19.9%) sought mental health support. Clinical duties related to urolithiasis management were reduced for most of the urologists, with elective procedures postponed and urolithiasis management confined to emergency conditions. In the absence of COVID-19 infection, 67 (35.1%) preferred to actively manage ureteral stones, whereas the remaining urologists preferred less invasive methods, such as conservative or instant drainage.

Conclusion: COVID-19 is hazardous to urologists in GCC countries, with 11.5% being infected and most reducing their clinical duties related to urolithiasis management. Although urolithiasis management in GCC countries during the COVID-19 pandemic was generally consistent with worldwide guidelines, some differences were observed, with further studies warranted to compare different management strategies.

Introduction

COVID-19 is a species of coronavirus that causes severe acute respiratory syndrome (SARS-COV-2) [1]. The first documented cases were in Wuhan, China, in September 2019. Infection subsequently spread worldwide, with the World Health Organization announcing an epidemic in March 2020 [2]. Since then, all countries worldwide have started to lockdown, with many activities being restricted, including flying, attending schools, participating in and watching sports activities, shopping at malls, and public gatherings. The health system has also been affected, with elective procedures and clinics being restricted. These restrictions have affected urologic practice and patient management [3]. Although the populations of the six countries in the Gulf Cooperation Council (GCC) have similar demographic characteristics, each country has devised its own lockdown strategy to deal with the pandemic. The present study explored the effects of the pandemic on the management of urolithiasis patients across the Gulf countries, as well as the impact of the pandemic on urologists practicing in these countries.

Methodology

A web-based survey was developed by a group of urologists from the six GCC countries. The survey, written in English, included 23 general and specific questions about COVID-19, including ten questions with free-response prompts. Upon developing the survey, it was sent to another few urologists as a pilot for validation.

The survey was sent to many urologists in the GCC countries who were easily approachable by the study investigators during the week of 10-16 May 2020. The 23 questions on the survey are detailed in Figure 1.

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Figure 1. Questions of the survey.

Results

Responses were received from 191 urologists, representing the six GCC countries. Of these respondents, 72 (37.7%) were from Qatar, 39 (20.4%) from Kuwait, 30 (15.7%) from the United Arab Emirates (UAE), 19 (9.9%) each from Oman and the Kingdom of Saudi Arabia, and 12 (6.3%) from Bahrain (Figure 2).

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Figure 2. The effect of COVID-19 on urologists in each country.

Of the 191 urologists, 145 (75.6%) worked in governmental hospitals, including 27 (14.1%) at academic centers, and 46 (24.4%) worked in private practice. The respondents differed in working experience, with 82 (42.9%) being consultants, 54 (28.3%) being specialists, nine (4.7%) being senior registrars, ten (5.2%) being registrars, four (2.1%) being assistant registrars, and 31 (16.2%) being urology residents. Of the respondents, 124 (64.9%) were general urologists, 42 (22.0%) were endo-urologists, and 25 (13.1%) were primarily interested in subspecialties in addition to urolithiasis.

Interestingly, 128 (67%) respondents changed their regular urology practice in response to COVID-19, 48 (25.1%) continued their routine practice, and 15 (7.9%) stopped practicing medicine following the lockdown. The lockdown reduced duty hours for 118 (61.8%) of the respondents and increased duty hours for 22 (11.5%), whereas 49 (25.7%) had almost the same number of duty hours, and two (1.0%) stopped practicing medicine.

Outpatient clinics and elective surgeries were closed or limited to minimize contact with patients. Only 26 (13.6%) reported no changes in the management of their clinics, whereas 37 (19.4%) closed their clinics, 91 (47.6%) changed to telemedicine phone consultations, four (2.1%) are consulting by video conference, and one (0.5%) is communicating with patients through the facility website.

Of the 191 respondents, 118 (61.8%) are not operating on patients infected with COVID-19, and 139 (72.8%) have stopped performing elective urolithiasis procedures. In contrast, 44 (23%) have reduced the number of elective urolithiasis procedures, whereas eight (4.2%) have not changed the number of procedures. Ninety-two respondents (48.2%) continue to perform the same number of emergency urolithiasis procedures, whereas 66 (34.5%) have reduced and 27 (14.1%) have increased the number of procedures. The remaining five (2.6%) urologists have stopped performing any operations, even emergency operations.

ESWL management was stopped by 98 (51.3%) of the urologists and reduced by 64 (33.5%) but remained unchanged by 18 (9.4%).Most of these respondents have changed the mode of anaesthesia to spinal anaesthesia. For example, 76 (39.7%) reported using spinal anaesthesia for all their patients and 16 (8.5%) for patients with proven COVID-19 infection. In contrast, 67 (35.1%) reported no change in anaesthesia preference in response to the pandemic.

To prevent infection, 112 (58.6%) urologists are screening their patients preoperatively, and 32 (16.5%) have worn full PPE routinely since the start of the pandemic.

In managing ureteral stones in patients lacking urinary tract infection and with unknown COVID-19 status, 67 (35.1%) urologists prefer more conservative management, 53 (27.7%) favour instant drainage followed by ureteroscopy after the easing of lockdown measures, 40 (20.9%) reported no change in management and 27 (14.1%) favour ureteroscopy for stone clearance. This is illustrated in Figure 3. These physicians were highly susceptible to COVID-19 infection, with 22 (11.5%) urologists found to be infected by positive swab results. Hospitals have been advised to support their employees psychologically, as evidenced by the 38 (19.9%) who received mental health support. Assessment of the impact of COVID-19 on these urologists showed that 107 (56%) were not affected, 55 (28.8%) had mild salary reduction, 25 (13.1%) experienced an almost 50% reduction in salary, and three (1.6%) stopped working because of the lockdown. Urologists are actively involved in COVID-19 management, with 84 (44%) shifting their medical practice from urology to volunteer in the treatment of COVID-19 patients. The impact of COVID-19 pandemic on urologists is illustrated in Figure2.

Discussion

About one-third of the respondents were from the state of Qatar. Response rates do not reflect the relative number of urologists in the six countries but may reflect the short time provided for the return of the survey. A large country like KSA requires more than one focal urologist, as well as additional time to reach urologists throughout the entire country. In 2016, approximately 257 urologists were estimated to be working in governmental hospitals (2), suggesting that our survey included only a small percentage of practicing urologists-most of the urologists who participated in the survey work in the governmental sector. In contrast, more than 50% of practicing urologists in the United States work in private practice [3].

The outbreak of COVID19 led most of the GCC to adopt lockdown measures, including preventing people from entering these countries during the outbreak period. Furthermore, medical services to treat COVID-19 patients were increased in most of these countries, including an increase in staff to provide these services. This led to an increase in staff exposure to COVID-19, increasing the incidence of COVID-19 among the staff. This, in turn, reduced the number of staff members available to treat COVID-19, requiring the deployment of urologists to work in COVID-19 facilities and reducing the ability to provide non COVID-19 related services.

Similar to other countries, most countries in the GCC have utilized telephone communications or telemedicine to manage outpatients, restricting surgery to emergency and oncology procedures. Also, the duty hours for physicians increased from 8 to 12 hours per day, making more staff members available to work in COVID-19 facilities. This was reflected in the survey results, as nearly two-thirds of the urologists were treating COVID-19 infected patients, whereas only about 25% continued practicing urology, which likely consists of emergency and oncology services. Similar changes were applied during the outbreak of COVID19 in Singapore [4].

EAU guidelines advise following local recommendations to test staff and patients for COVID-19 if resources are available [5]. Nearly two-thirds of the respondents are testing their patients for COVID-19 preoperatively, and only 16% reported wearing full PPE. This does not conform to EAU guidelines, perhaps because of a relative lack of availability of the test kits or the equipment for full PPE. The EAU guidelines advise full PPE, irrespective of the COVID status of the patient [5].

Testing patients for COVID-19 is crucial because asymptomatic patients from Wuhan, China, who tested positive for COVID-19 before surgery, had a postoperative mortality rate of 20% [6].

Since the EAU guideline considered that surgery is harmful to the patients if he is tested COVID positive, this should result in a change in the practice of management of urolithiasis. Our survey showed inconsistencies in the management of urolithiasis during the COVID-19 pandemic. For example, 20% of urologists surveyed did not alter their management of ureteral stones in the absence of infection, with only 38% selecting conservative management (Figure3).

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Figure 3. Management of ureteral stones in patients lacking urinary tract infection and with unknown COVID-19 status.

Studies have advised that, whenever possible, patients should be treated non-surgically or surgery should be deferred until the demands for ventilators and inpatient beds are reduced [7]. The EAU guidelines recommend treating intermediate priority patients if the capacity is available but not during COVID-19 surge [5].

Healthcare workers are members of the frontline response team and are therefore highly susceptible to infection. The WHO–China Joint Mission on COVID-19 reported that by 20 February 2020, there were 2,055 laboratory-confirmed cases of COVID-19 among healthcare workers, with 22 (1.1%) deaths [8].In Italy, at least 2,629 health workers, or 8.3% of all infected individuals, have been infected with coronavirus since the pandemic broke out in February [9]. In our survey, 11.5% of respondents were laboratory confirmed as having COVID-19. In addition to the infection itself, COVID-19 may be an independent risk factor for mental health problems in health care workers, including depression, anxiety, insomnia, and distress [10,11]. The WHO recommendations for health workers mention various hazards, including exposure to the pathogen, long working hours, psychological distress, fatigue, occupational burnout, stigma, and physical and psychological violence [12]. The WHO recommendations include providing access to mental health and counselling resources. This is supported by our survey, which found that 20% of the respondents had been provided mental health support by their facilities. The lockdown has also had an economic impact on the urologists working in this region. For example, our survey found that 75% of the urologists working in government hospitals, as well as some in private hospitals, were mildly affected economically, whereas around 15% experienced a greater economic impact, which may worsen the psychological impact of the pandemic on health care workers. The effect of COVID-19 on urologists in each country is illustrated in Figure 2.

Despite surveying a relatively large number of respondents, the results of this survey were limited by its narrow distribution among urologists in the region, which may have led to uneven distribution and collection bias. This may have been avoided had the survey been kept open for a longer period. However, this survey explored the common and variable practices among the health care organizations in the Gulf countries and emphasized the need for further studies to compare various practice strategies. The survey also showed the relatively high risk of COVID-19 infection to urologists, which warrants further evaluation by well-designed observational studies.

Conclusion

COVID-19 is hazardous to urologists in GCC countries, with 11.5% being infected and most reducing their clinical duties related to urolithiasis management. Although urolithiasis management in GCC countries during the COVID-19 pandemic was generally consistent with worldwide guidelines, some differences were observed, with further studies warranted to compare different management strategies.

References

  1. Gorbalenya AE, Baker SC, Baric RS, de Groot RJ, Drosten C, et al. (2020) The species Severe acute respiratory syndrome-related coronavirus: Classifying 2019-nCoV and naming it SARS-CoV-2. Nature Microbiology 5: 536-544.
  2. Otaibi KE (2016) Challenge facing the urologist in Saudi Arabia in the future. Urol Ann 184-188.
  3. The State of the Urology Workforce and Practice in the United State (2018).
  4. Chan MC, Yeo SEK, Chong YL, Lee YM (2020) Stepping Forward: urologists’ Efforts during the COVID-19 outbreak in Singapore. EurUrol 78: 38-39. [crossref]
  5. European Association of Urology. https://uroweb.org/wp-content/uploads/EAU-Guidelines-Office-Rapid-Reaction-Group-An-organisation-wide-collaborative-effort-to-adapt-the-EAU-guidelines-recommendations-to-the-COVID-19-era.pdf
  6. Lei S, Jiang F, Su W, Chen C, Chen J, Wei W, et al. (2020) Clinical characteristics and outcomes of patients undergoing surgeries during the incubation period of COVID-19 infection. EClinicalMedicine 21: 100331. [crossref]
  7. Stensland KD, Morgan TM, Moinzadeh A, Cheryl T, Briganti A, et al. (2020) Consideration in the triage of urologic surgeries During the COVID-19 pandemic. EurUrolEpub 77: 663-666.
  8. World Health Organization. 2020. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19)
  9. Psychiatry Res (2020) Jun; 288: 112972. Published online 2020 of Apr 13. doi: 10.1016/j.psychres.2020.112972. PMCID: PMC7152886
  10. SaiSpoorthy M, KarthikPratapa S, Supriya M (2020) Mental health problems faced by healthcare workers due to the COVID-19 pandemic- A review. Asian J Psychiatr 51: 102119. [crossref]
  11. Jianbo Lai, Simeng Ma, Ying Wang, ZhongxiangCai, Jianbo Hu, et al. (2020) Factors Associated With Mental Health Outcomes Among Health Care Workers Exposed to Coronavirus Disease 2019. JAMA Netw Open 3: 203976.
  12. Coronavirus disease (COVID-19) outbreak: rights,roles and responsibilities of health workers, including key considerations for occupational safety and health. 18 March 2020. COVID-19: Schools, businesses and institutions. WHO reference no.: WHO/2019-nCov/HCW_advice/2020. https://apps.who.int/iris/rest/bitstreams/1272583/retrieve.

Facemasks are Not Effective for Preventing Transmission of the Coronavirus

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DOI: 10.31038/JNNC.2020321

 

On February 29, 2020, Jerome Adams, the Surgeon  General of  the United States, tweeted that, “They [facemasks] are NOT effective in preventing general public from catching coronavirus.” Within a few months, he and the Centers for Disease Control and Prevention (CDC) were stating that facemasks are effective for preventing transmission of viral illnesses in the community, and within a short time, governments in the United States and elsewhere were mandating the wearing of facemasks in public. The explanation for this reversal in policy focused on asymptomatic carriers in public. However, the evidence from Randomized Controlled Trials (RTCs) indicates that surgical facemasks have no effect on the transmission of viral illnesses in the community. Based on their physical characteristics, one would not expect surgical facemasks to reduce viral transmission by asymptomatic carriers. The size of a coronavirus is about 0.1 microns and the pore size of surgical masks is in the range of 50-100 microns: the pores are 500-1000 times the size of the virus. Aerosol droplets are about 3 microns in diameter, so surgical masks would not be expected to block them either.

A common rationale for wearing masks in public is that their purpose is not to protect you from others, but to protect others from you if you are an asymptomatic carrier: this is illogical. How can a mask protect someone else from you if it does not protect you from someone else? Also, asymptomatic carriers are, by definition, not coughing or sneezing in public, except very infrequently. Normal breathing and speaking emits primarily aerosols not droplets; droplets are the main concern for transmission of the coronavirus in public. Infectious symptomatic carriers who are emitting virus-laden droplets should be in quarantine, therefore it is not necessary to mandate facemasks to protect the public from them.

Four meta-analyses published to date report that no Randomized Controlled Trial (RCT) has ever shown a significant difference in viral transmission rate with and without facemasks in the general public. Brainard, Jones, Lake, Hopper and Hunter  [1] reviewed 3 RCTs   and found no difference in any of them; Cowling, Zhou, Ip, Leung, and Aiello [2] reviewed 4 RCTs and found no difference in any of them; Xiao, Shiu, Gao, Wong, Fong, Ryu and Cowling [3] reviewed 10 RCTs and found no difference in any of them; and Aggarwal, Dwarakananthan, Gautam and Ray [4] reviewed 9 RCTs and found no difference in any of them. These meta-analyses by four different groups from around the world have not found a single RCT that demonstrates a protective effect of facemasks for viral transmission in the general public. In discussing the Xiao et al. [3] Meta-analysis, Greenlagh, Schmid, Czypionka, Bassler and Gruer [5] said that, “…the authors conclude that there was no significant reduction in influenza transmission with the use of facemasks.” The situation, then, is not that there is a lack of evidence: there is replicated, controlled evidence that facemasks do not reduce viral transmission in the community.

For the sake of discussion, what if we made an assumption that facemasks reduce the rate of viral transmission in the community by 5%? For this discussion, we will bear in mind that there is no evidence that facemasks reduce transmission by even  this  much.  Further, let’s assume that the infection rate in the community is 5% and the mortality rate for infected healthy people under 60 is 0.1%. This would mean that wearing facemasks would reduce one’s risk of infection as a healthy person under 60 from 5% to 4.75%; the risk of death from COVID-19 would drop from 0.005% to 0.00475% due to wearing facemasks. This does not seem like a sufficient risk reduction to justify mandatory facemasks in public.

Wearing masks is not terribly inconvenient, but it does have  costs in terms of dollars, an energy burden from manufacturing and distribution, and pollution pressure on landfills, bodies of water and the environment in general. Given these considerations, and the evidence from RTCs, it would seem that mandates for wearing facemasks in public should be, at the least, reduced to recommendations, until there is definitive evidence that they are effective. For any other topic in medicine, one would expect a consensus to exist if all the available RTCs and meta-analyses found that a given intervention has no effect on the target problem. One would expect authorities to state that there is no need for the intervention. If the same standards were applied to public wearing of facemasks for COVID-19, there would be neither a mandate nor a recommendation for them. As discussed recently, facemask policies are only one of many problems with how medical authorities have handled the COVID-19 epidemic; many public health recommendations and statements have not been based on science [6].

References

  1. Brainard JS, Jones N, Lake I, Hooper L, Hunter P (2020) Face masks and similar barriers to prevent respiratory illness such as COVID-19: A rapid systematic review. Medrxiv doi:10.1101/2020.04.01.20049528.
  2. Cowling BJ, Zhou Y, Ip DK, Leung GM, Aiello AE (2010) Face masks to prevent transmission of influenza virus: a systematic review. Epidemiology of Infections 138: 449-456. [crossref]
  3. Xiao J, Shiv EYC, Gao H, Wong JY, Fong MW, et al. (2020) Nonpharmaceutical measures for pandemic influenza in non-healthcare settings – personal protective and environmental measures. Emerging Infectious Diseases 26: 967-975.
  4. Aggarwhal N, Dwarakananthan V, Gautham N, Ray A (2020) Facemasks for prevention of viral respiratory infections in community settings: A systematic review and meta-analysis. IndianJournal of Public Health 64: 192-200.
  5. Greenhalgh T, Schmid MB, Czypionka T, Bassler D,  Gruer L (2020) Facemasks  for the public during the COVID-19 crisis. British Medical Journal 369: m1435. [crossref]
  6. Ross CA (2020) Thoughts on COVID-19. Journal of Neurology and Neurocritical Care 3: 1-3.

Therapeutic Effects of Ozone Therapy that Justifies Its Use for the Treatment of COVID-19

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DOI: 10.31038/JNNC.2020314

Abstract

SARS-Cov2, the virus causing COVID-19, is distributed globally since December 2019, causing a pandemic and there are currently no specific treatments available. Patients evolve differently and extreme cases have fatal outcomes after 10 days of being infected. The virus is known to cause Acute Respiratory Distress Syndrome (ARDS). Cytokine storm is considered to be one of the major causes of ARDS and multiple-organ failure. Due to the high lethality of SARS-CoV2 infections and its economic and social impact, it is necessary to seek new therapeutic procedures. It has been demonstrated that ozone therapy produces a significant improvement in blood flow and oxygenation of ischemic tissues. Also, ozone can achieve an equilibrium between Nrf2 and NF-κB factors, modulating the oxidative stress and the expression of pro-inflammatory cytokines. In clinical studies, ozone has a significant role in the treatment of pulmonary and vascular diseases. Today, ozone therapy represents the most practical approach for integrating standard therapies to achieve homeostasis. Therefore, due to the ozone therapeutical effects, it can be proposed as an adjunct therapy in SARS-CoV-2. Three randomized control trials (NCT04359303, NCT04370223 and NCT04444531) are pending classification and approval to start in Spain, one in Iran (IRCT20190618043923N4) and two more (NCT04366089 and NCT04388514) started in Italy one month ago.

Keywords

COVID-19, Immunomodulation, NF-κB, Nrf2, Oxidative stress, Ozone therapy

Introduction

According to the World Health Organization (WHO), viral diseases continue to emerge and represent a serious issue to public health. An epidemic of cases with unexplained low respiratory infections was first reported to the WHO Country Office in China, on December 31, 2019. The new virus was called SARS-CoV-2 and the disease cause was a “COVID-19” an acronym of “coronavirus disease 2019” [1]. Many of these patients deteriorated rapidly and required intubation and mechanical ventilation. Mortality rates are assumed to be around 3.7%. There is currently no effective treatment [2,3]. The therapeutic strategies to deal with the infection are only supportive. Prevention, aimed at reducing transmission rates within the community is our best weapon.

COVID-19 has characteristics of two known syndromes [4,5]:

• Macrophage activation syndrome [6]: a life-threatening complication characterized by hypercytokinemia (cytokine storm) with multi-organ failure. It is characterized by an uncontrolled activation and proliferation of T lymphocytes and macrophages, producing extensive tissue damage as endothelial lesions that lead to the production of microthrombi. Laboratory abnormalities include a decrease in white blood cells, platelet and hemoglobin. There is a production of a high level of transaminase, a marked increase in ferritin, and evidence for intravascular coagulation activation. The protagonist of this storm is mainly interleukin 6 (IL-6) which promotes the differentiation of B lymphocytes. The cytokine storm also stimulates the production of acute-phase proteins and further plays a role in thermoregulation, bone maintenance and the function of the central nervous system. During inflammatory diseases, infections, autoimmune disorders, cardiovascular diseases and some types of cancer, there is an increase in IL-6.

• Antiphospholipid syndrome [7]: it is an autoimmune system disorder that manifests clinically as recurrent venous or arterial thrombosis. This also alters the homeostatic regulation of blood coagulation. The D-dimer is elevated in most patients with pneumonia and other indicators of coagulation are abnormal. Thrombocytopenia is also observed, which seems to be associated with a poorer prognosis. Analytically, the presence of high levels of ferritin in the blood is striking. They appear to respond to an acute inflammatory process. Liver enzymes also tend to be elevated. The Fe2+ released into the blood, in the presence of hydrogen peroxide produces hydroxyl radicals (Fenton reaction). This is extremely toxic, causing oxidative damage, mainly pulmonary, but also systemic. The lung tissue damage stimulates the monocyte-macrophage system which contributes significantly to the inflammatory process. Taking into account all the ozone therapeutical properties, which will be explained below, it can be proposed as an adjunct therapy for patients with COVID-19.

Ozone Therapy and its Mechanism of Action

Ozone (O3) is an allotropic form of the element oxygen, containing one more atom than atmospheric oxygen. It is particularly unstable and decomposes spontaneously into diatomic oxygen, which, in practice, makes it very difficult to transport and store. Ozone therapy has been used for therapeutic purposes since the beginning of the last century and its use is increasingly demanded nowadays. It is characterized by the simplicity of its application, its great effectiveness and with good tolerance. International reports of adverse reactions to the application of ozone therapy place it among the lowest incidences with 0.0007% [8,9]. Ozone, at therapeutic doses, is capable of producing a small, transitory and controlled oxidative stress that stimulates a group of depressed biological functions without causing any adverse effect. This ozone’s preconditioning effect is capable of rebalancing the upset redox state in the organism [10]. Biochemically, when blood is exposed to ozone for several minutes, it reacts immediately with different molecules present in biological fluids, namely antioxidants, proteins, carbohydrates and, preferentially, polyunsaturated fatty acids (Criegee reaction), leading to the formation of alpha-hydroxy- hydroperoxides, hydrogen peroxide, ozonides and aldehydes such as 4-hydroxynonenal. These are important signaling molecules, with crucial roles modulating inflammation, cell proliferation, cell growth and cell death [11].

These alkenals can activate a nuclear transcriptional factor, called nuclear factor erythroid 2-related factor 2 (Nrf2) present in the cell cytoplasm bound to Keap-1 protein. Such a protein has -NH2 and, mainly, -SH groups (Cys273 and Cys288) which, by binding alkenals [for example 4-hydroxynonenal (4-HNE)] at picomolar levels, causes a conformational change favoring the dissociation of Nrf2. This is then imported into the nucleus where, after forming a heterodimer with Maf (musculoaponeurotic fibrosarcoma) protein, interacts with the Antioxidant Response Element (ARE) on DNA. Consequently, the synthesis of several antioxidative enzymes (superoxide dismutase, catalase, glutathione reductase, glutathione S-transferases, NADPH- quinone oxidoreductase, heat shock protein 70, phase II enzymes and Heme-oxygenase-1) are upregulated in various organs [12]. Also, reduces iron overload, and subsequent oxidative stress that is induced by elevated ferritin [13]. The increase of antioxidant capacity is the crucial step to counteract the chronic inflammation typical of diseases aggravated by chronic oxidative stress. An improvement of the antioxidant response has been reported in patients with asthma and Chronic Obstructive Pulmonary Disease (COPD), as emphysema, treated with ozone therapy [14-16]. Specifically, improvements were seen in IgE levels, inflammatory response, respiratory tests and clinical status. Also, in patients with rheumatoid arthritis, ozone has exerted beneficial effects [17,18].

This ozone efficacy not only may be explained through its actions on cytokine control (diminished IL-1, IL-6 and tumor necrosis factor α-TNFα) but also can reestablish cellular redox balance. It is known that reactive oxygen species can function as a second messenger to activate the nuclear transcription factor NF-κB, which orchestrates the expression of a spectrum of genes involved in the inflammatory response. Nrf2 is able to modulate inflammation through multiple mechanisms, such as the regulation of redox homeostasis and the suppression of pro-inflammatory genes, either directly or through the interaction with NF-κB [19]. Inflammation increases local and systemic Reactive Oxygen Species (ROS) level while ROS enhance inflammation. The Nrf2-mediated ROS-homeostatic control can break this vicious cycle. Nrf2 reduces inflammation by preventing the recruitment of RNA polymerase II to start gene transcription of pro-inflammatory cytokines IL-6 and IL-1β [20]. The capability of Nrf2 to maintain redox homeostasis would prevent DNA damage, preserve proteostasis, and improve mitochondrial function while suppressing acute and chronic inflammation [20]. The antioxidant and anti-inflammatory effects of ozone involve activation of Nrf2, which is thus considered as a key factor for the efficacy of ozone treatments. A previous study reported that ozone preconditioning significantly reduced NF-κB expression and inhibited inflammatory responses in liver ischemia/reperfusion injury [21]. Ozone can achieve an equilibrium between Nrf2 and NF- κB, modulating the expression of pro-inflammatory cytokines with an important effect in cytoprotection (Figure 1) [20].

JNNC-3-1-304-g001

Figure 1. Ozone and its relation with Nrf2 and NF-κB.
Ozone, at therapeutic doses, is capable of producing a small, transitory and controlled oxidative stress. The nuclear transcription factor Nrf2 is usually present within the cytosol as a complex with Keap-1 protein. The 4-HNE (ozone active metabolite) binds to Cys 151 of Keap1 and suppresses the constitutive inhibition of Nrf2, which then translocates into the nucleus. After binding to Maf, Nrf2 binds to ARE and switches on the synthesis of highly cytoprotective enzymes (SOD, catalase, GSH, heme-oxygenase-1, HSP, etc) maintaining a redox balance. NF-κB is also a redox- regulated transcription factor, involved in inflammation, immune function, cellular growth and apoptosis. In resting, it exists in an inactive form complexed with the inhibitor IκB. In the presence of oxidative stress, H2O2 (ozone active metabolite) activates a tyrosine kinase that phosphorylates IκB and causes its detachment from the inactive complex. The heterodimer moves promptly from the cytosol into the nucleus, where it regulates gene expression forming new proteins such as cytokines (IL-1, IL-2, IL-6, IL-10, TNF-α), COX-2, iNOS, adhesion molecules (ICAM), tissue factor, immunoregulatory molecules. At the same time, these two pathways inhibit each other at their transcription level via protein-protein interactions or through secondary messenger effects [19]. Nrf2 opposes the transcriptional upregulation of proinflammatory cytokine genes. Nrf2 binds to the proximity of inflammatory cytokine genes, including IL-6 and IL-1β, and inhibits their transcription. Nrf2 pathway also inhibits NF-κB mediated transcription by preventing the degradation of IκB-α. At the same time, Nrf2 upregulates the expression of genes coding antioxidant proteins. Similarly, NF-κB mediated transcription reduces the Nrf2 activation by reducing the ARE gene transcription, among other factors. Therefore, it can be considered that ozone is involved in the balance between these two transcription factors.
Nrf2, nuclear factor erythroid 2-related factor 2;Keap1, Kelch-like erythroid cell-derived protein; Maf, musculoaponeuroticfibrosarcoma; ARE, antioxidant response element; HO-1, heme oxygenase-1; 4-HNE, 4-Hydroxynonenal; HSP, Heat shock protein; SOD, superoxide dismutase; GSH, reduced glutathione; H2O2, hydrogen peroxide; TNF, tumor necrosis factor; COX-2, cyclooxygenase-2; ICAM, intercellular adhesion molecule; iNOS, inducible nitric oxide synthase.

Besides, Nrf2-activator may attenuate the Toll-Like Receptor (TLR) mediated aberrant inflammation by activation of intrinsic cytoprotective proteins and suppression of pro-inflammatory mediators. Hence, these two major signaling pathways may interact differentially and their cross-talk can be manipulated to regulate inflammation [22]. TLR activation is critical in the initiation of an inflammatory response against pathogens by triggering the production of inflammatory cytokines, enhancing adaptive immunity [23]. Simultaneously, a negative feedback mechanism also exists that could prevent the over-activation of TLR signaling that may otherwise result in chronic inflammation or autoimmunity. Nrf2 activation interferes with the expression of pro-inflammatory proteins and suppresses inflammation. The interaction of TLR and Nrf2 helps in the regulation of the inflammation process. The linkage between TLR signaling and Nrf2-Keap1 pathway may serve as a bridge between immune regulation and oxidative stress responses through the regulation of inflammation [22]. It has been demonstrated that ozone preconditioning improved renal inflammation and damage by blocking the activation of TLR4-NF-κB pathway in renal ischemia/ reperfusion injury. Also, ozone significantly reduced the mRNA level of TNF-α, IL-1β, IL-6, ICAM-1 (Intercellular Adhesion Molecule 1) and MCP-1 (monocyte chemoattractant protein 1) [24]. On the other hand, medical ozone, in vitro, has proven to be effective against viruses, bacteria, fungi and spores, destroying cells membrane and viruses envelop [25].

Ozone Therapy and its Positive Effects in the Treatment of Patients with COVID-19

Among the therapeutic effects of ozone therapy that favors the positive evolution of patients with COVID-19 are:

– Ozone improves oxygen metabolism increasing cellular oxygenation. Improving the hexose-monophosphate shunt, due to the activation of 2,3-DPG which, by binding to the β–chain of hemoglobin (Hb), causes a shift to the right of the Hb dissociation curve. This enhances the release of oxygen in the hypoxic tissues. There is also an improvement of the glycolytic pathway on erythrocytes significantly increasing their ATP content [11,13], recovering the elasticity of the red cell membrane thus improving blood rheology and capillarity [26]. There is a significant improvement in blood flow and oxygenation of ischemic tissues due to ozone treatment [27-30]. This is due to Nitric Oxide (NO), S-nitrosothiols cooperating with Carbon Monoxide (CO) and released prostacyclin [31,32]. Different preclinical and clinical studies have demonstrated the effect of ozone in modulating the NO levels and its importance in the protection of the vascular endothelium cells [32-34].

– Ozone is capable of inducing the release and modulation of interferons and related cytokines. Also, stimulates antioxidant defense systems, counteracting the state of hyperinflammation, cytokine storm and oxidative stress, suffered by patients with COVID-19. This is achieved through the increase in Nrf2 factors and restoring cellular redox balance [35,36]. There is also the activation of heme oxygenase-1 (HO-1) by increasing the release of CO and bilirubin. This contributes to reducing inflammation [37]. Several preclinical and clinical studies report a decrease in proinflammatory cytokines as IL-1, IL-6, TNFα, as well as ICAM-1, MCP-1, among others [24,38-45]. Ozone was able to modulate the phagocytic cells in peripheral blood and the mechanisms on how messengers can activate immunological response leading to the therapeutic biological effects [46,47]. This is a very positive effect on COVID-19 infection. The inflammatory response is a hallmark of severe SARS-CoV-2 infection, cytokine storm can lead to the death of these patients. The protective effect of ozone therapy was achieved by its anti-inflammatory property through the modulation of nucleotide- binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome, enhancing the antioxidant activity of Nrf2 and inhibiting apoptosis [48,49]. The NLRP3 inflammasome is a critical component of the innate immune system that mediates caspase-1 activation and the secretion of proinflammatory cytokines IL-1β/IL-18 in response to microbial infection and cellular damage. On the other hand, activation of Toll-Like Receptor (for example TLR4) by SARS-CoV-2 causes a biochemical cascade that begins with the formation of pro-IL-1 cleaved by caspase-1 and followed by activation of the inflammasome. IL-1 is secreted outside the macrophage, mediating lung inflammation, fever and fibrosis, and provoking severe respiratory problems [50]. It has been demonstrated that ozone preconditioning protected the rat kidney from reperfusion injury via modulation of the TLR4-NF-κB pathway [24].

– COVID-19 patients suffer from microthrombi due to increased viscosity and erythrocyte aggregation, among other factors. Ozone has an antiplatelet effect, increases some prostacyclins (like PGI2) leading to vasodilatation, as well as modulates antithrombin III [31,51]. All these effects, in conjunction with better blood circulation, can help to decrease the hypercoagulation phenomena present in these patients.

– Ozone can block the virus’s ability to replicate by balancing the cellular redox state, through the control of Nrf2 [52,53]. SARS-CoV-2 cell entry depends on Angiotensin-Converting Enzyme 2 (ACE2) and Transmembrane protease, serine 2 (TMPRSS2). SARS spike protein S will attach to ACE2. Following attachment to ACE2, viral entry requires S protein priming, which is performed by TMPRSS2 cleaving S protein. TMPRSS2 activity is essential for viral spread and pathogenesis in the infected host, and TMPRSS2 inhibitors have been investigated as a potential therapeutic target for SARS-CoV-2. Nrf2 activators have an important role in reducing viral pathogenesis via inhibiting virus entry through inhibit TRMPSS2 [54,55]. Nrf2 activators may offer multiple ways to regain control of important pathways to increase resistance and slow viral replication. Application of an NRF2 activating agent, ACE2 mRNA was down-regulated 3.5-fold and TMPRSS2 was down-regulated 2.8-fold in human liver-derived HepG2 cells [56]. Exacerbated lung injury in Nrf2−/− mice was associated with increased pulmonary expression of inflammatory cytokines (TNF-α, IL-1β, IL-6) and with decreased pulmonary antioxidant and detoxifying enzymes relative to Nrf2+/+ mice [57]. Furthermore, pretreatment with the Nrf2-ARE inducer sulforaphane significantly attenuated Respiratory Syncytial Virus (RSV)-induced bronchopulmonary inflammation, epithelial injury and pulmonary viral expression in Nrf2+/+ mice [58]. Results from the study confirmed an association of oxidative stress in RSV pathogenesis and provide compelling evidence for an important regulatory role of Nrf2-ARE as a host defense mechanism against RSV disease. Another study found an inverse relationship between the levels of Nrf2 expression and influenza A viral entry and replication within nasal epithelial cells [59]. In response to experimentally applied mechanical ventilation, greater levels of lung alveolar and vascular permeability and inflammatory responses were found in Nrf2−/− compared to Nrf2+/+ mice [60]. In mice, Nrf2 deficiency caused augmented ovalbumin-driven airway inflammation and hyperresponsiveness. In this study, the enhanced allergic response in Nrf2−/− mice was associated with more pronounced lung mucus cell hyperplasia, eosinophilic infiltration, increased Th2 cytokines IL-4 and IL-13 and suppressed multiple antioxidants relative to Nrf2+/+ mice [61]. In an experimental sepsis model, Nrf2 deficiency increased the inflammation and mortality of mice against bacterial endotoxin (LPS)- and cecal ligation and puncture-induced septic shock [62]. This indicates that Nrf2 is a novel modifier of sepsis that determines survival by mounting an appropriate innate immune response. Data, therefore, suggest that Nrf2-ARE activators exert protective effects on LPS-induced inflammation, and suggested their potential therapeutic role for intervening sepsis syndrome. Taking into account that ozone stimulates Nrf2 [28,36,37,63], this could be an important physiological mechanism to block endogenous COVID-19 reduplication by preventing contact with receptors of SARS-CoV-19 through downregulation of ACE2 and TMPRSS2, inactivating the ability of the virus to enter cells [55]. The re-equilibration of the cellular REDOX state achieved with the ozone therapy is also important in the induction of cytokines synthesis in monocytes and lymphocytes and in the release of HO-1 and heat shock proteins which are potent activators of the immune system [12,64].

Conclusion

In summary, the positive aspect of ozone therapy is the ability to activate several defense mechanisms that cooperate to regain a normal redox system and a modulation of the NFκB/Nrf2 pathway. Today, ozone therapy represents the most practical approach for integrating standard therapies to achieve homeostasis. Therefore, due to the ozone therapeutical effects, it can be proposed as an adjunct therapy in SARS- CoV-2. Three randomized control trials (NCT04359303, NCT04370223 and NCT04444531) are pending classification and approval to start in Spain, one in Iran (IRCT20190618043923N4) and two more (NCT04366089 and NCT04388514) started in Italy one month ago.

Highlights

Ozone Therapy can be used for the treatment of COVID-19.

Ozone can achieve an equilibrium between Nrf2 and NF-κB,
modulating oxidative stress and pro-inflammatory cytokines.

Ozone counteracts hyperinflammation, cytokine storm and oxidative stress.

Ozone improves oxygen metabolism, blood flow and oxygenation of ischemic tissues.

Author Contributions

SMC – works on the conceptualization, drafting, editing and revision. JAMM, AHM, FJHT and JBN – work on the conceptualization and critical review of the manuscript. All authors have approved the final version of the manuscript.

Conflict of Interest

The authors declare they have no conflict of interest.

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Farmers Market Fruit & Vegetable Rx Program Shows Clinically Significant Quality of Life Outcomes Using Standardized SF-36 Health Survey

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DOI: 10.31038/PEP.2020121

Abstract

Introduction: Fruit and vegetable prescription programs at farmers markets have shown some statistically significant changes in health markers. To date, little is known about whether these programs also improve Quality of Life (QoL). The current study examined if QoL improvements occurred after participation in a fruit and vegetable prescription program.

Methods: Our team of volunteer clinicians enrolled a cohort of 101 low-income adult participants over three years. Participants self-identified as food insecure and had previously been diagnosed with a diet-related disease. Each received a “prescription” to purchase fruits and vegetables from the local farmers market. Participants attended monthly clinic visits and attended plant-based cooking classes. Demographic, baseline and post-program outcome data (SF-36; Medical Outcomes Survey Short Form) were collected.

Results: All SF-36 subscales and composite scales showed statistical significance indicating subjectively improved quality of life/health among program graduates. SF-36 Role-Physical, Bodily Pain, Energy-Vitality and Role-Emotional subscales also demonstrated Reliable Changes (RCIs) indicating clinically significant outcomes across these domains of function. Individually, 32% and 27% of graduates exceeded the RCI for the Physical Composite Scale and Mental Composite Scales, respectfully.

Conclusion: This is the first study to apply the SF-36 RCI measure to assess generic quality of life outcomes of a fruit and vegetable prescription program based at a farmers market. It uniquely adds to the growing evidence supporting the benefits of improved access to healthy food through collaborative community interventions. Study participants reported both statistically significant and clinically meaningful improvements in functional health and QoL.

Keywords

Vegetable prescription, Clinical significance, Quality of life, Dietary behavior, Farmers market, Reliable change index

Introduction

Fruit and vegetable prescription programs such as the FVRx® have emerged as health interventions at farmers markets throughout the United States [1]. Such programs are premised on research showing a favorable link between increased fruit and vegetable consumption and markers of health [2-4]. Fruit and vegetable prescription programs also rely on emerging community food system studies examining public health collaborations designed to improve fresh produce accessibility and consumption [5,6].

The produce prescription model has been studied as a medical intervention for diet-related chronic diseases [7], as a measure of the psychosocial benefits of farmers markets [8,9], a catalyst for nutrition education [10], a vehicle for healthy food access in low-income/low-access neighborhoods [11,12] and a learning milieu for healthcare professionals [13]. Researchers have collected quantitative biological data as well as qualitative self-reported data [14,15]. Studies have also reported outcomes of improved health perception among participants [16].

Previously reported data from year-end program evaluations of the five FVRx programs in Georgia (of which our cohort was a part) conducted by Wholesome Wave Georgia showed both socioeconomic and health benefits. In 2017, this statewide data showed that, from baseline to the end of the six-month program, the percentage of program participants reporting that “food often didn’t last” and there “wasn’t money to buy more food” decreased by 79% (22% to 4%) across all sites. Further, the overall percentage of program participants reporting that they had often gone hungry “due to lack of money for food” decreased by 89% (44% to 11%) over the course of the program [17]. The 2018 program evaluation of this statewide data found that over the relatively short six-month program timeframe, Body Mass Index decreased 1.4% and waist circumference decreased 3.3% [18].

As fruit and vegetable prescription programs grow in number and design, studies must also seek to discover the clinical significance [19] resulting from community food-healthcare partnerships. In other words, do participants self-report evidence of improved quality of life upon completing these community-based programs?

This three-year study examined whether low-income/low- access adult graduates of an FVRx program experienced favorable improvement in their subjective Quality Of Life (QoL) and function. To our knowledge, this is the first study to assess subjective change in QoL and function in fruit and vegetable prescription programs based at a farmers market using the Medical Outcomes Survey – Short Form 36 (SF-36), a standard in generic quality of life outcome metrics.

Methods & Materials

Participants

On average, 34 adults enrolled in the program annually, for three years in sum total, at no personal cost. The majority of participants came from areas with low access to healthy food options, self- identified as food-insecure and had been previously diagnosed with a diet-related disease such as obesity, hypertension, diabetes, and/or heart disease.

FVRx Program Description

The program targeted change in dietary behavior among participants and included three required components: (a) monthly clinic visits, (b) weekly farmers market attendance, (c) and plant-based cooking classes. The program was a six-month per year intervention conducted over three years (2017-2019).

Outcome Measurement

We selected the SF-36 as the outcome measure. The SF-36 is widely considered a gold standard in generic quality of life metrics, quantifying disease burden, and measuring patients self-report of functional health. It has been utilized in 4000+ peer reviewed scientific publications – of which more than 400 were randomized controlled clinical trials – and judged to be a useful tool in evaluating benefits of treatment interventions [20]. It is suitable for age ≥ 14 and requires 5-10 minutes to complete. The data is summarized in two higher order factors, termed Physical Health and Mental Health Composites which are equated to patients’ attitudes regarding overall physical and mental health status. Eight subscales are generated, reflecting physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. Each subscale attempts to quantify a patient’s attitude in specific physical or health domains. For example; the Role-physical scale measures how much a patient believes that their daily activity is limited by physical dysfunction whereas the energy-vitality scale ranges from feeling “tired and worn out” to “full of energy and pep”.

Procedures

Prior to enrollment, we outlined the program’s attendance expectations and incentive component before participants signed informed consent forms. Volunteer healthcare providers (i.e., physicians, nurses, registered dietitians), accompanied by first-year medical students, collected baseline program-related information to include demographics, SF-36 surveys, and other data not reported herein during the initial visit. Self-reporting surveys were issued with literacy support when needed. Clinicians provided healthy eating and lifestyle education and then wrote a “prescription” for each participant to redeem for only fruits and vegetables at the farmers market. The prescription had a no-cash value of $7/person/week for four weeks each month, based on family size. For example, an adult participant with a family of four received redeemable market tokens equivalent to
$28/week ($112/month).

Participants returned to the clinic monthly where volunteer clinicians offered encouragement, provided general health and nutrition education, and renewed prescriptions. Participants attended a weekly farmers market to redeem their prescriptions for fruits and vegetables, sold by local farmers, and attended a minimum of four required plant-based cooking classes at no cost. Health educators at the farmers market provided nutrition information and cooking demos for the general public, of which participants were a part. Farmers also provided recipes and preparation tips to help demystify lesser-known seasonal fruits and vegetables.

When absent from the program, participants reported schedule conflicts, illness and lack of transportation as the most common reasons for not attending. If absent from the farmers market three weeks in a row, and/or if non-compliant with clinic or cooking class attendance, participants were listed as non-completers and unenrolled. An average 26% of participants were recorded as non-completers. Participants who completed the above-mentioned requirements and the post-SF-36 on (or within one month of) the sixth clinic visit were considered program “graduates”/completers.

Statistical Analysis

Descriptive statistics of demographic and SF-36 outcome data at baseline and at six-month follow-up were calculated. Per Protocol (PP) and Intent to Treat (ITT) analyses using SPSS 26.0 statistical package were employed to investigate change in SF-36 scores occurred after participation in the FVRx six-month program. Within subject paired sample t-tests were used to examine if statistical differences existed in each of the eight subscales or either of the two composite scales on the SF-36 after six months of FVRx program participation relative to baseline. Given the exploratory nature of this study, a conventional p-value of ≤0.05 was selected to denote statistical significance. Adjunctively, RCI also were calculated for each participant’s SF-36 subscales and composite summary scales to appreciate where clinically significant change may have also occurred. RCI calculations have been validated using normative data for general populations and several disease states [21].

Results

Of the 101 participants enrolled, 75 completed the program and had a full data set. There were no significant differences between completers and non-completers in any measured demographic, health, or socioeconomic variable. Our average participant was a female (82%) African American (76%) who earned less than $2000/month (74%) and lived in a low access area. A majority were uninsured or covered by a federal insurance program (68%) and received supplemental benefits (64%) (Table 1).

Table 1: Demographics.

Demographics

% of Sample

Age 18-29

7.90%

30-39

11.9%

40-49

19.8%

50-59

34.70%

60+

25.7%

Sex Male Female

17.80%

82.2%

Race Hispanic,

6.9%

Asian, Asian American

1%

American Indian, Alaskan Native

3%

Black, AA, or Carib. American

76.20%

Hawaiian, Pacific Islander

13.90%

Other

5.90%

Educational background

10.90%

< High school diploma

19.80%

High school or GED certificate

36.60%

Some college or tech school

15.80%

2 year college or tech degree

12.90%

4 year college or tech degree

4%

>4 college degree

Employment status

Student

2%

Working part-time

10.90%

Working full-time

25.70%

Not employed, or homemaker

15.80%

On disability

27.70%

Retired

12.90%

“Other”

5%

Health Insurance

Uninsured

23.80%

Medicated or Medicare

44.60%

Insured through employer

21.80%

Insured, private insurance

4%

Other

5%

Income level

<$1000/month

38.60%

$1001 – $1300/month

19.80%

$1301 – $1700/month

4%

$1701 – $2000/month

11.90%

$2001 – $2400/month

6.90%

$2401 – $2700/month

5.90%

$2701 – $3000/month

5%

$3001 – $3400/month

5%

> $3401

3%

Supplemental benefits

No

35.60%

Received

64.40%

Average (SD) # of people aged 0-17 Living in home: 1.5 (1.6), ranging from 0 to 9.

Note 1: Final sample size was N = 101, reflecting 35 participants from year 2017, 39 from year 2018, and 27 from year 2019.

All eight of the SF36 individual subscales and both of the composite scales showed statistical significance in a favorable direction implicating improved self-reported quality of life/health direction after program participation. This was true in both the PP (all P-values ≤0.002) and ITT (all p-values ≤0.028) analyses (Table 2 and Figure 1).

Table 2: Descriptive Statistics and Over-Time Comparisons for SF-36.

Baseline

Follow-up

Paired Sample

Paired Sample

RCI

t-test

t-test

N = 101

N = 75

with case-wise

with missing

SF-36 Variable

AVG (SD)/Min-Max

AVG (SD)/Min-Max

deletiona

values replacedb

+

Physical Functioning

60.8 (28.5)/0-100

66.1 (26.1)/10-100

-3.16 (p = .002)

-2.23 (p = .028)

Role-Physical

47.5 (43.1)/0-100

66.7 (39.1)/0-100

-3.99 (p < .001)

-4.96 (p < .001)

Yes

Bodily Pain

47.6 (25.8)/0-100

57.6 (25.0)/0-100

-3.68 (p < .001)

-4.44 (p < .001)

Yes

General Health

51.8 (20.1)/5-100

61.5 (19.0)/20-97

-5.36 (p < .001)

-6.00 (p < .001)

Energy-Vitality

45.6 (20.6)/0-90

57.1 (19.7)/10-100

-5.29 (p < .001)

-6.01 (p < .001)

Yes

Social Functioning

64.5 (25.2)/0-100

77.2 (22.3)/13-100

-5.10 (p < .001)

-5.28 (p < .001)

Role-Emotional

58.8 (42.2)/0-100

80.4 (36.0)/0-100

-4.10 (p < .001)

-5.40 (p < .001)

Yes

Mental Health

71.6 (18.3)/28-100

77.1 (14.7)/40-100

-3.41 (p = .001)

-3.53 (p = .001)

PCS Composite

37.4 (11.7)/13-65

41.1 (10.8)/12-66

-4.78 (p < .001)

-4.28 (p < .001)

MCS Composite

47.3 (10.5)/28-68

52.5 (9.4)/25-68

-4.98 (p < .001)

-5.58 (p < .001)

aPer protocol analysis, in that IF data was missing at time 2, THEN entire case was deleted. Total of 26 cases had missing data at time 2 resulting in a final sample of N = 75.
bIntention to treat analysis, in that all 101 participants data was included with missing data at time 2 imputed by using the average of the group. N = 101.
Note 2: N = total sample size. AVG = computed average. SD = Standard Deviation. Min = Minimum Value. Max = Maximum Value. RCI + = Reliable Change Index (Jacobson &Truax, 1991) was exceeded, indicating that as a group a reliable change in overall obtained scores at follow-up relative to baseline had occurred.

PEP-1-2-107-g001

Figure 1. SF-36 Overtime Comparison.

As a cohort, the Role-Physical, Bodily Pain, Energy-Vitality and Role-Emotional scales all exceeded established SF-36 RCI for clinically meaningful change. Individually, 32% and 27% of graduates were judged to have demonstrated reliable change on the SF-36 Physical Composite Scale (PCS) and Mental Composite Scale (MCS), respectively (Figure 2).

PEP-1-2-107-g002

Figure 2. SF-36 Reliable Change.

Discussion

Fruit and vegetable prescription programs rely on emerging studies of community food systems. Farmers markets may provide uniquely collaborative spaces in which community health improvements can occur. Fruit and vegetable prescription programs at farmers markets are also premised on research showing a favorable link between increased fresh produce consumption and markers of health. However, little research has been published to date that has investigated the impact of participation in such programs on self- reported quality of life and function.

The present study highlights several important findings. First, the majority (75%) of participants were able to complete a six-month FVRx program requiring monthly clinic in-person check-ins and attendance in several cooking classes. The relatively low attrition rate supports the contention that this kind of programming is both viable and well regarded by study participants who have low access to healthy food options, are food insecure, and are challenged by medical morbidities including obesity, hypertension, diabetes, and/or heart disease. Second, these results highlight that after completion of the program, study participants self-reported experiencing improved physical functioning, bodily pain, general health, level of energy/pep, social functioning, and mental health while also experiencing less impact on their ability to perform expected roles because of emotions or physical challenges (all results were statistically significant). Third, over and above the aforementioned statistically significant differences, appreciation of RCIs also would highlight that clinically meaningful change in a favorable direction occurred in the areas of bodily pain experienced, level of energy/pep, and ability to perform expected roles.

Several study limitations are evident. First, as a cohort study, this endeavor was limited by lack of a control or comparison group as well as some variations in the year-to-year program requirements and implementation. We also recognize that while the socioeconomic mix of program cohorts, educators and farmers is not specifically addressed in this study, it likely represents a significant influence on its outcomes and would be a valuable area for future study. Future studies should also include a control or comparison group and be powered/ designed to estimate quality adjusted life years and cost effectiveness.

In summation, our study adds to the growing body of literature supporting fruit and vegetable prescription programs and expands knowledge of the benefits of increasing access to healthy food and wellness education within the milieu of farmers markets. The convergence of partners involved in providing these community- based collaborative health programs represents a behavioral health treatment approach with a wide variety of players and motivations. We believe increasing access to these types of programs should be a national priority.

Acknowledgements

Dozens of community members gave voluntary time as program participants; we appreciate their commitments. We also thank Augusta Locally Grown for program coordination; Wholesome Wave Georgia for program funding & design; Augusta District Dietetic Association for volunteer clinicians; Medical College of Georgia  & Augusta University for volunteer students; Harrisburg Family Healthcare for hosting; St Luke United Methodist for transportation; EAT Local CSRA & Icebox Ministries for cooking education; Women in Philanthropy, Community Foundation of the CSRA, Good Neighbor Ministries, Women’s Health of Augusta and Reid Memorial Presbyterian for education program funding. Finally, we thank all the farmers of the Veggie Park Farmers Market.

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  11. Marcinkevage J, Auvinen A, Nambuthiri S (2019) Washington State’s fruit and vegetable prescription program: improving affordability of healthy foods for low- income patients. Prev Chronic Dis 16: 180617.
  12. Saxe-Custack A, LaChance J, Hanna-Attisha M, Ceja T (2019) Fruit and vegetable prescriptions for pediatric patients living in Flint, Michigan: a cross-sectional study of food security and dietary patterns at baseline. Nutrients 11: 1423. [crossref]
  13. Forbes JM, Forbes CR, Lehman E, George DR (2019) “Prevention produce”: integrating medical student mentorship into a fruit and vegetable prescription program for at-risk patients. Perm J 23: 18-238. [crossref]
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Observational Study of the Effect of the Hydroxychloroquine/Azithromycin Combination in Patients Hospitalized for a Severe Form of COVID-19

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DOI: 10.31038/JPPR.2020322

 

What is Already Known about This Subject?

The discussion on the efficiency of the hydroxychloroquine/azithromycin combination remains open. To date, no randomized trial has demonstrated the efficiency of this combination in patients with a severe form of COVID-19.

What This Study Adds?

We report the results of a non-randomized observational study compared hydroxychloroquine/azithromycin combination to any antiviral treatment for patients with a severe form of COVID-19. We warn of the difficulty of interpreting these results in the absence of randomization.

Abstract

Following the demonstration in vitro of the efficiency of a synergistic effect of hydroxychloroquine (HCQ) associated with azithromycin (AZI) against the SARS-CoV-2, some studies have aimed to evaluate its efficiency in a clinical setting. We present the results of a non-randomized observational study of patients admitted for a severe form of COVID-19 disease who have been treated by HCQ/AZI after collegial physicians’ decision. Of the 306 patients included (average age: 72.8 years), 53 received the HCQ/AZI association. Univariate analysis shows in non-survivors a higher average age, more severe clinical signs on admission (lung invasion rate> 50%, Dyspnea and creatinine>133µmol/L) and more comorbidities (cerebrovascular accident, chronic kidney disease, immunodeficiency).We evaluated the efficiency of the HCQ/AZI treatment on a population (n=96) with comparable characteristics (age, risk factor, gravity…). If mortality of the patients treated with HCQ/AZI seems different in this sub-study population (HCQ/AZI: 0% vs. Other: 8%), the methods of the study and its size do not allow the identification of a statistically significant difference (p=0.122).

At this time of the epidemic, the HCQ/AZI must be evaluated in a randomized trial at the right and safe dosage.

Introduction

At the end of 2019, a new coronavirus, designated SARS-CoV-2, was causing an epidemic of respiratory diseases in China. The city of Wuhan (China) went into full confinement on January 23, 20201. On March 12, 2020, the World Health Organization (WHO) declared the COVID-19 pandemic. The importance of the number of symptomatic patients and the particular gravity of some of them lead the Hospitals to reorganize in emergencies on an almost daily basis both at the structural, organizational and medical level. Among the antiviral treatments likely to be effective on the symptoms of SARS-CoV-2, three molecules or associations stood out: remdesivir, the fixed combination ritonavir/lopinavir and (hydroxy)chloroquine associated or not with azithromycin [1].

In mid-March, remdesivir and the ritonavir/lopinavir combination were announced as a complete disruption by the laboratories producing them. The French Ministry of Health then supervised the off-label use of hydroxychloroquine, conditioning it to severity criteria and subject to a collegial decision by the medical profession. We present the results of a monocentric, observational, retrospective study aimed at evaluating the efficiency of the hydroxychloroquine/azithromycin combination on the COVID-19 disease.

Methods

All patients hospitalized at our center for a severe form of COVID-19 disease were included in the study.The diagnosis of COVID-19 disease combined the recording of symptoms (fever, caugh, fatigue, myalgia, headache, dyspnea, diarrhea, nausea, vomiting, anorexia, anosmia, aguesia, dizziness, fall, hypoxemia) with a SARS-CoV-2 reverse-transcriptase–polymerase-chain-reaction (RT-PCR) and/or standard low dose CT imaging.The following characteristics were sought in the study population: age, body mass index (BMI), active or history of smoking, chronic kidney/heart/respiratory disease, hypertension, diabetes mellitus, dyslipidemia, cerebrovascular accident and immunodeficiency (including cancer under treatment). The home drugs treatment of interest were sought: angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) calcium-chanel inhibitor, diuretics, betablockers, corticosteroids and aspirin. We have listed antivirals under evaluation:remdesivir, hydroxychloroquine (HCQ), azithromycin (AZI), ritonavir/lopinavir.The severity of the COVID-19 stage of the patients included was assessed on the basis of at least one of the following criteria: dyspnea, O2 saturation ≤93%, radiological pulmonary infiltrates >50% at 24-48 hours of admission [2].

HCQ/AZI

The dosage of HCQ/AZI was: HCQ (D1-D10; 600mg per day in 3 doses) combined with azithromycin (D1: 500mg in 1 dose; D2-D5: 250mg per day). Only patients not on dialysis, with no contraindication to HCQ/AZI treatment (e.g. severe kidney failure, widening of the QTc wave) received treatment with HCQ/AZI after collegial physician decision. All patients on HCQ/AZI underwent an electrocardiogram before initiating treatment. Once treatment was started, an electrocardiogram was performed daily during hospitalization, as well as a determination of serum potassium, magnesemia and blood sugar. In order to reduce the biases linked to the care of patients, to the comorbidities, to the typology of the medical service (e.g. palliative care, geriatry) and to the contraindication of HCQ/AZI treatment (dialysis), we have make a sub-study. In this sub-study only patients treated in internal medicine were included and we have excluding dialysis patients.

Clinical Outcomes

Critical disease defined by death or transfer to intensive care unit (ICU) and death alone were the two main outcomes.

Statistical Analysis

Continuous data are summarized as mean (standard deviation) and categorical data as frequency (percentage). For univariate comparisons T-test and Chi-2 tests were used as appropriate to compare differences between non-critical and critical disease or survivor and non-survivor. The multivariate analysis used logistic regression ajusted on age, sex, body mass index (BMI), chronic heart disease, hypertension, diabetes mellitus, chronic kidney disease, hemodialysis, chronic lung disease (asthma or chronic obstructive lung disease), personal history of stroke, current or former tobacco use, treatment with immunosuppressive drugs (including anticancer drugs), creatine and C-reactive protein (CRP) levels, percentage of lung affected on CT-scan, low oxygen saturation, dyspnea, oxygen flow. A two-sided p value < 0.05 was considered statistically significant. Statistical analyses were performed with SPSS 26.0 package. Neither patients nor the public were involved in the conception or conduct of the study.

Results

Between March 15 and April 15, 2020, 314 patients were admitted into the different wards. Eight patients were transferred to another hospital and were considered loss of follow-up: 6 were transferred to another region to vacant intensive care beds and 2 were taken care of for extracorporeal membrane oxygenation. The median age was 75.6 ± 14.5 years. The number of days between the onset of symptoms and hospitalization was 6.6±7.8 days. Men were a little more represented (54%).

Comorbidities

Table 1 shows major comorbidities recorded on admission. The most common were chronic heart disease (71%), hypertension (58%), dyslipidemia (36%), chronic kidney disease (27%), diabetes mellitus (26%), immunodeficiency (21%) and chronic respiratory disease (19%). Eighty nine percent of the patients have comorbidity with an average number of comorbidities of 4.1±2.3. Three per cent (8/306) of patients were current smokers and 10% were former smokers.It can be noted that 26% of patients have a BMI> 30kg/m2.

Table 1: Demographic findings of patients on admission.

Demographic data

Total
(N=306)

Survivor
(N=231)

Non-survivor
(N=75)

p-value *

Age – yr

75.6 ± 14.5

72.8 ± 14.7

84.0 ± 9.9

<0.0001

Sex (male sex)

54%

55%

49%

0.394

Weight (kg)

74.8 ± 15.8

76.3 ± 15.7

70.2 ± 15.4

0.007

Body mass index (kg/m2)

26.8 ± 5.0

27.2 ± 5.0

25.6 ± 4.9

0.03

BMI<25 kg/m2 (%)

59%

61%

50%

0.11

BMI 25–29.9 kg/m2 (%)

32%

34%

28%

0.396

BMI≥30 kg/m2 (%)

26%

27%

22%

0.376

Nursing home resident (%)

13%

10%

23%

0.003

Severity and mortality

Death (%)

25%

0%

100%

–

ICU transfer (%)

3%

3%

3%

0.871

Critical cases (Death or transfer to ICU) (%)

27%

3%

100%

<0.0001

Time from symptom onset to admission (days)

6.6 ± 7.8

7.2 ± 7.5

4.5 ± 8.5

0.013

Length of stay in hospital (days)

11.3 ± 10.0

12.2 ± 9.4

8.5 ± 11.3

0.005

Time between admission and ICU transfer (days)

1.1 ± 1.7

1.2 ± 1.7

1.0 ± 1.9

0.802

Comorbidities (%)

Hypertension

58%

55%

67%

0.065

Diabetes mellitus

26%

27%

25%

0.797

Chronic heart disease

71%

67%

84%

0.005

Dyslipemia

36%

33%

44%

0.094

Chronic respiratory disease

19%

20%

15%

0.276

Chronic kidney disease

27%

23%

43%

0.001

Dialysis

4%

3%

7%

0.232

Immunodeficiency

21%

16%

36%

<0.0001

Cerebrovascular accident

20%

16%

32%

0.002

At least one comorbidity

89%

87%

97%

0.009

Smoking status (%)

Current smoker

3%

3%

1%

0.424

Former smoker

10%

9%

15%

0.134

Home drug treatments (%)

ACE inhibitors

20%

19%

24%

0.31

ARBs

22%

22%

21%

0.955

Calcium-chanel inhibitor

23%

22%

24%

0.729

Diuretics

27%

22%

44%

<0.0001

Betablockers

31%

27%

44%

0.007

Corticosteroids

5%

3%

11%

0.008

Aspirin

30%

25%

45%

0.001

*p-value univariate statistical test between Survivor VS Non-Survivor. – : statistical test non applicable.

Home Drug Treatments

Home drug treatments included beta-blockers (31%), aspirin (30%), diuretics (27%), calcium channel blockers (23%), ARBs (22%), ACE inhibitors (20%) and corticosteroids (5%). No patient was treated by non-steroidal anti-inflammatory drugs (Table 1).

Severity of the Clinical Case

At the admission, 43% of the patients presented a C-reactive protein >100mg/L, 43% an oxygen saturation £93%, 21% a creatinine>133µmol/L and 7% of the patient presented a proportion of lung invasion rate>50% (average percentage of invasion: 29%±18) (Table 2). Among the 306 patients eligible for analysis, 250 had a lung CT scan and 213 a RT-PCR.

Symptoms

The most common symptoms were dyspnea (67%), fever (60%), fatigue (59%), cough (51%), diarrhea (30%), myalgia (18%) and dizziness/fall (17%). Only 6% of patients reported ageusia/anosmia on admission (Table 2).

Table 2: Clinical, laboratory and radiographic findings of patients on admission.

Symptoms at onset of illness (%)

Total
(N=306)

Survivor
(N=231)

Non-survivor
(N=75)

p-value*

Fever

60%

62%

55%

0.266

Cough

51%

52%

51%

0.898

Fatigue

59%

58%

60%

0.812

Myalgia

18%

20%

11%

0.058

Headache

8%

9%

4%)

0.184

Dyspnea

67%

64%

77%

0.028

Diarrhea

30%

33%

21%

0.058

Nausea or vomiting

9%

11%

1%

0.008

Anorexia

11%

12%

11%

0.809

Anosmia or ageusia

6%

7%

1%

0.054

Dizziness. fall

17%

16%

19%

0.657

Hypoxemia (oxygen saturation < 93%)

43%

40%

55%

0.024

Inpatient drug treatments (%)

Hydroxychloroquine with azithromycin

17%

22%

4%

<0.0001

Hydroxychloroquine alone

2%

1%

3%

0.417

Azithromycin alone

4%

5%

1%

0.184

Lopinavir with Ritonavir

4%

4%

5%

0.593

Oxygen therapy

87%

86%

91%

0.269

Invasiveventilation

9%

9%

9%

0.858

Laboratory findings

PCR confirmed diagnosis (%) n=213

79%

75%

90%

0.023

C-reactive protein (mg/L)

101.2 ± 83.6

95.9 ± 83.5

118.0 ± 82.3

0.05

CRP<5 mg/L (%)

5%

6%

1%

0.108

CRP<100 mg/L (%)

57%

60%

47%

0.051

CRP 100–199 mg/L (%)

28%

25%

36%

0.075

CRP≥200 mg/L (%)

15%

14%

17%

0.64

Creatinine (µmol/L)

115.7 ± 110.4

103.6 ± 93.2

154.6 ± 147.6

0.001

Creatinine ≥ 133µmol/L (%)

21%

17%

33%

0.003

Radiologic findings (n=250)

Percentage of lung affected on the CT scan (%)

29 ± 18

28 ± 17

31 ± 22

0.253

Proportion of lung affected on the CT scan > 50%(%)

7%

5%

14%

0.028

Typical CT-scan (%)

14%

15%

7%

0.125

Bilateral pulmonary infiltration (%)

46%

48%

36%

0.120

Ground-glass opacities (%)

29%

33%

14%

0.008

Analysis of Non-survivors as Compared with Survivors

Tables 1 and 2 show the distribution of demographic characteristics and coexisting conditions among survivors and non-survivors. Non-survivors were older (p<0.0001) and had a greater prevalence of chronic heart disease (p=0.005), cerebrovascular accident (p=0.002), chronic kidney disease (p=0.001), and immunodeficiency (p<0.0001). Among medication, aspirin (p=0.001), corticosteroids (p=0.008), betablockers (p=0.007) and diuretics (p<0.0001) were more commonly used by non-survivor patients. The non-survivors were faster hospitalized after the first symptoms (4.5±8.5 days vs. 7.2±7.5 days). Among non-survivors mortality rate was of 25% and transfer to ICU was of 3%. Laboratory and radiologic findings for non-survivors reveal fewer signs at admission of renal dysfunction (creatinine≥ 133µmol/L; p<0.003) and lung invasion rate (>50%; p<0.028). The multivariate analysis of factors associated with non-survival reveals that increasing age was a strong predictor of in hospital mortality after adjusting for major comorbidity (per additional year, OR 1.083; p=0.003) (Figure 1). Stroke history (OR:2.983; p=0.027), immunodeficiency (OR:4.665; p=0.002) and percentage of the lung affected on the CT scan were also statistically associated with increased hospital mortality (OR:1.032 per additional percent of lung affected; p=0.009). The other factors don’t show a significant implication on the patient outcomes.

JPPR-3-2-315-g001

Figure 1. Mortality by age.

Antiviral Treatment

Fifty-three patients received the HCQ/AZI association, 13 the lopinavir/ritonavir association, 12 azithromycin alone and 5 HCQ alone.The HCQ/AZI have been administered an average of 7.9±3.1 days of treatment. Among 16 patients who did not receive the 10 days of treatment, the causes were: transfer to ICU (N=6), widening of the QTc wave (N=6; occurring between 1 and 8 days after initiation of treatment), renal failure (N=1), death (N=2; after 1 and 3 days of treatment), pseudo-cerebellar syndrome attributed to viral damage combined with HCQ (N=1). Thepatients treated by HCQ/AZIhad severe form of COVID-19 (9% of lung affected on CT-scan), were younger patient (13 years) and tend to have more comorbidities except diabetes and immunodeficiency.Percentage of lung affected on CT-scan was the only variable statistically associated with death or ICU transfer (OR:1.033 [1.002-1.064], p=0.039) among patients admitted into the two internal medicine ward where HCQ-AZI were used. The sub-study (N=96) which evaluate the efficacy of treatment with HCQ/AZI for the patients admitted into the two internal medicine units included 96 patients. There was no significant difference in demographic, comorbidities, smoking status, home drug treatment and laboratory/radiologic findings between the treated and untreated population. If the mortality of patients treated with HCQ/AZI seems different, this result is not statistically significant (0% vs. 8%; p=0.122).

Discussion

The COVID-19 situation worldwide, as of 1 July 2020 based on the data transmitted by the different countries is 10 446 353 cases of COVID-19 including 511 037 deaths [1]. If the number of new cases seems to decrease in Europe, the world wide situation continues to worsen. The average incubation period for COVID-19 is 5 days [3]. The interval from symptom onset the hospital admission is 6, days in our study. The average age of patients in our study (75.6 years) is higher than the studies currently published (47-73 years) with a male preponderance3. The clinical manifestation of COVID-19 is various. We found standard symptoms in hospitalized patients included: dyspnea, fever, asthenia, cough, diarrhea, muscle ach and dizziness/fall. Anosmia ageusia may be identified in only 6% of patients. If comorbidities presented by 89% of our patients are among the most common (hypertension, diabetes mellitus), they are present in a remarkably high rate of our patients (chronic heart disease>70%, chronic kidney disease > 25%, immunodeficiency>20%) [4,5]. Obesity seems to play a special role affecting more than 25% of our patients. Obesity or excess ectopic fat deposition are suspected of unifying risk factor for severe COVID-19 infection, reducing both protective cardiorespiratory reserve as well as potentiating the immune dysregulation that appears, at least in part, to mediate the progression to critical illness and organ failure in a proportion of COVID-19 patients [6]. However, it should be noted that it does not appear as a factor of death. Concerning the long-term treatments taken by the patient, the patients treated with aspirin, diuretics, betablockers or corticoids are significantly higher in the non-survivor group. But, it is difficult to attribute excess mortality to these treatments, since they are generally used to manage the comorbidity previously mentioned. The search for a predictive sign of worsening of a patient’s condition at admission is a major issue in medical management. There is an excess mortality in patients more older (Figure 1), patients who on admission have dyspnea, oxygen saturation £ 93%, a lung invasion rate> 50% or a creatinine> 133 µmol/L. These elements are warning signs for the physician supported by other publications on the subject [7]. On the other hand, on the advanced side on antiviral treatment, there has been no notable progress to date. Among the treatments discussed, remdesivir, the ritonavir/lopinavir and HCQ/AZI combination were the first treatments offered in France. For reasons essentially of availability, hydroxychloroquine associated or not with azithromycin has become one of the only therapeutic options in the absence of any evidence of effectiveness. Gautretet al. published the first result of the HCQ/AZI efficiency in COVID-19 patients [8]. They demonstrated on a series of 80 patients an undetectability of viral load at the nasopharyngeal level in 83% of patients on day 7, 93% on day 8 [9]. Respiratory samples are negative in 97.5% of patients on day 5. However, patients in this study had a low rate of comorbidity for an average age of 52.5 years. They do not appear to be the most at risk of complications given the current state of knowledge. Thus, only 53.8% (43/80) had a CT-scanner lung disease and 15% (12/80) had oxygen need.This population appears to have a relatively mild impairment compared to our study population. In agreement with the relative viral RNA load reduction, in vitro tests show a cytopathic effect of SARS-CoV2 could be observed in only 16% (5/31) wells at 60 h post infection after HCQ/AZI exposition as compared to 100% (13/13) in positive controls [9]. Rosenberg et al. publish an observational study to report adverse events and mortality of HCQ and/or azithromycin among patients with COVID-19 (Number of patient: 735 with HCQ/AZI, 271 with HCQ, 211 with azithromycin, 221 any treatment – similar age:61.4 to 65.5 average) [10]. Cardiac arrest was more frequent in patients who received HCQ with azithromycin, compared with patients who received neither drug, even after adjustment. Moreover, treatment with HCQ, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality. Mahevas et al report a study carried out on 181 patients requiring oxygen therapy excluding patients transferred to ICU [11]. In their study, 15 patients were treated with the HCQ/AZI combination, none were transferred to ICU and none died.

The treatment of patients was done according to modalities (collegial doctor’s decision) and within deadlines close to ours (7 days after the onset of symptoms). The mortality reported in this study is lower than ours. This can be attributed to the exclusion of patients without ICU need and the average age of the population (60 years vs. 75 years), even if the predictors of aggravation are relatively similar (CRP, percentage of pulmonary invasion). Interestingly, the authors put into perspective the importance of treatment with an antiviral during the virus contamination phase. However, HCQ exhibits immunomodulatory properties through its action on interleukin 1,2 and 6, TNFa and the inhibition of toll-like receptors. This explains its effectiveness in certain autoimmune pathologies which in the case of the inflammatory storm identified in certain forms of COVID-19 could be of theoretical interest. Nevertheless, the latest published clinical data, consistent with our series, point out that during the inflammatory phase (usually on the second week of symptoms) this treatment should have any effectiveness. Side effects, particularly of the heart, in patients with fragility induced by viral infection remain a warning point for physician using the HCQ/AZI combination. In our cohort of treated patients 11.3% (6/53) had heart rhythm problems. As rhythm disturbances were not systematically sought in the untreated group, it is difficult to conclude on an increase in disorders due to COVID-19 disease or to antiviral treatment. A study of 201 patients demonstrated that Baseline QTc intervals did not differ between patients treated with chloroquine/HCQ (monotherapy group) vs. those treated with combination group (chloroquine/HCQ and azithromycin) (440.6 ± 24.9 ms vs. 439.9 ± 24.7 ms, p = 0.834) [12]. More recently Mehraet al. presented a multinational registry analysis carried out on the largest population studied to date (96 032 patients; mean age 53.6±17.6; oxygen saturation <94%; 19.9% of non-survivors patient) [13]. This article which seemed to make everyone agree was retracted a few days after its publication by its authors. However we should note that the authors reported an excess mortality in patients treated with combination of HCQ (main dosage 587mg±128mg during 4.3±2.0 days) with a macrolide (azithromycin or clarithromycin; dosage not communicated) as well as a de-novo ventricular arrhythmia in 8.1% of patients treated (versus 0.3% of untreated patients). We find a similar percentage of ventricular rhythm disorders (11.3% vs. 8.1%) in our patients with a more advanced age (75 years vs. 54 years), a comorbidity rate, predictors of severity and duration longer treatment (7.9 vs. 4.3 days). However, we did not find an increase in the mortality of patients treated with the HCQ/AZI combination. In view of these various elements, it remains necessary to remain cautious. The need for QT interval monitoring remains necessary. We draw attention to the difficulty to interpret the results of a non-randomized observational study. Indeed, in the absence of randomization, the mortality comparison data in the group treated by HCQ/AZI and the group not treated are impacted by many biases. Thus, if mortality seems different in the total study population (HCQ/AZI: 6% vs. Other: 28%) and in the sub-study population (HCQ/AZI: 0% vs. Other 8%), it is distorted by populations that are not comparable (age, risk factor) and different treatment methods desired or not by physicians. We no longer observe any significant difference after identifying and taking into account the biases inherent in this type of study. As a conclusion, the question of the efficiency and safety of the HCQ/AZI combination in the treatment of COVID-19 disease remains open pending the results of randomized clinical studies (Figure 1 and Tables 1-3).

Table 3: Multivariate analysis of factors associated with death.

Demographic data

Adjusted OR (CI 95%)

p-value**

Age – yr

1.083(1.028-1.142)

0.003

Sex (male sex)

0.52 (0.216-1.25)

0.144

Body mass index (kg/m2)

0.971 (0.886-1.063)

0.518

Nursing home resident

1.758 (0.457-6.757)

0.411

Comorbidities

Hypertension

1.923 (0.758-4.881)

0.169

Diabetes mellitus

0.566(0.201-1.591)

0.281

Chronic heart disease

1.032 (0.34-3.129)

0.955

Chronic respiratory disease

0.759 (0.274-2.103)

0.595

Dialysis

2.045 (0.295-14.149)

0.469

Immunodeficiency

4.665 (1.73-12.58)

0.002

Cerebrovascular accident

2.983 (1.13-7.875)

0.027

Smoking status

 

Current smoker

3.564 (0.31-40.92)

0.307

Former smoker

1.448 (0.389-5.393)

0.581

Symptoms at onset of illness

Dyspnea

1.332 (0.521-3.406)

0.549

Hypoxemia (oxygen saturation < 93%)

0.936 (0.383-2.284)

0.884

Laboratory findings

Creatinine (µmol/L)

1.002 (0.999-1.006)

0.182

Radiologic findings

Percentage of lung affected on the CT scan (%)

1.032 (1.008-1.057)

0.009

Conflict of Interest

The authors declare they have no conflict of interest.

Ethics Approval

The study has been approved by the ethics committee of the GroupeHospitalier Saint Vincent (GRE 2020-01). Written informed consent has been waived in light of the urgent need to collectclinical data.

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A Critical Evaluation of the Single-Use Policy of Endodontic Instruments

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DOI: 10.31038/JDMR.2020331

Abstract

Endodontic treatments involve accessing a sterile or non-sterile pulp chamber and root canal content, following an inflammation of the pulp or bacterial colonization of the pulp chamber and root canals, as a septic complication of decay. For this purpose, stainless steel instruments were developed in the last century and Ni-Ti files more recently, serving for different purposes during different procedures and manoeuvres having the unique goal to clean and seal the root canal. For this purpose stainless steel and more recently, nickel-titanium (Ni-Ti) instruments have been developed. These instruments not only increased the speed of the treatment but also managed to assure a proper shape of the canal preparation and subsequently, of the canal filling. Being so useful, reliable, resistant, and ultimately, not cheap, the initially single-use instruments got to be reused by a wide number of practitioners. The present review critically evaluates the single-use policy of these instruments, debating on aspects like cross-infection, mechanical aspects, sterilization protocols and its effect in these instruments, highlighting what is known at the moment about it.

Keywords

Endodontic, Policy, Prions, Review, Root-canal, Single-use

Introduction

Endodontic treatments involve accessing a sterile or non-sterile pulp chamber and root canal content, following an inflammation     of the pulp or bacterial colonization of the pulp chamber and root canals, as a septic complication of decay. For this purpose, stainless steel instruments were developed in the  last  century  and  Ni-Ti  files more recently, serving for different purposes during different procedures and manoeuvres having the unique goal to clean and seal the root canal respecting the biologic and mechanical principles stated by Schilder [1]. Newer (Ni-Ti) files not only increased the speed of the treatment but also managed to assure a proper shape of the canal preparation and subsequently, of the canal filling. Being so useful, reliable, resistant, and ultimately, not cheap, the initially single-use instruments got to be reused by a wide number of practitioners for at least 5 times, with great success, being assured by the manufacturers that both files and the tooth are safe. There are reports of file reuse on 12 [2] or 24 [3] extracted roots having medium curvature.

Worldwide legislations are not prohibiting the reuse nor imposing the single-use, with very few exceptions. Medicine and Health Care Regulatory Agency in the United Kingdom have considered that an instrument used in the root canal should not be reused on multiple patients, not even on the same patient on a later occasion, and hence should be discarded [4]. The Department of Health has critically evaluated the importance of a single- use endodontic instrument during dental treatment, to supply the patients with a safe and infection controlled environment [5]. There was obvious evidence that showed the risks associated with the reuse of endodontic files, including secondary Transmissible Spongiform Encephalopathy disease (TSEs) and improper debris control [6]. But besides these aspects, it has also been shown that the use of endodontic file decontamination and sterilization methods can play a role in the development of various risks such as file fracture.

In modern dentistry, all clinicians should consider infection control maintenance, as it cannot be dismissed [7]. Microorganism has an obvious rule for developing infected necrotic pulp tissue which was isolated from infected root canals [8]. Fusobacterium nucleatum, Porphyromonas Gingivalis, and Streptococcus mutants are the most common bacteria that were isolated from infected root canals [7]. Van Eldik [7] in his research done on stainless steel and NI-TI files, demonstrated the effect of thermal steam sterilisation and mechanical cleaning techniques on the microbial elimination. They concluded that there were no bacteria detected on new files or following steam sterilisation. On the other hand, the ultrasonic bath eliminated the majority but not all of the bacteria. Assaf, Mellor, and Qualtrough [9] illustrated that mechanically cleaning endodontic files by using washer-disinfectant treatment can lead to incomplete organic debris removal from endodontic files’s surfaces.

Aspects Related to Prion Disease

The prion proteins were discovered in 1982 as a fatal neurodegenerative protein with different groups like PrP. This can cause scrape veterinary diseases and veterinary Creutzfeld-Jacob Disease (vCJD) in humans [6,10]. Creutzfeld-Jacob Disease can be transmitted by direct blood contact or transfusion [10]. The Prion protein has a high resistance to many disinfectant and sterilisation techniques such as chemical, thermal, ionizing radiation, and ultraviolet decontamination resistance, with a high binding capacity to metal surfaces, compromising the sterilisation process especially in dried contaminated tissue on metal or glass surfaces [6,11,12].

The prion disease accumulates in the lymphoreticular tissue and the nervous system. Early diagnosis of human prion disease can be detected by lymphoreticular biopsy of tonsils, spleen, and lymph nodes [13]. Few studies have linked re-used endodontic files with transmissible spongiform encephalopathy (TSEs) which is a group of brain and nervous system diseases in humans and animals that can develop in the presence of prion prusiner protein. Although, no obvious research stated that Creutzfeldt-Jakob Disease (vCJD) has been transferred to humans during dental treatment [6] one of prion’s possible way of transmission from the brain to the mouth tissues and vice versa is assumed to be by means of prion protein accumulation in the trigeminal ganglia of patients with this disease [14]. There were four cases reported of possible transmission of CJD infection by means of blood transfusions but no evidence so far that CJD is contagious either by normal or sexual contact [15,16]. Even so, before seeking any endodontic treatment, it is mandatory to obtain from all patients appropriate family and medical history as well as sterilise the endodontic files for optimal infection control [11,17].

Currently, in the United Kingdom, The Health Department has considered root canal treatment files as single–used instruments and should be segregated immediately after clinical use [4,18]. Dental instruments (except files) used on patients with or ‘‘at increased  risk’’ of CJD can be handled in the same way as those used in any other low-risk surgery, can be reprocessed according to best practice and returned to use [4]. Other instrument types for which a reliable cleaning regime is not available should also be considered single- use types. Although the Department of Health UK guidelines does not recommend any special protocols  for  prion  decontamination, an improved cleaning process along with multiple cycles of vacuum steam sterilization procedure should be followed [19].

Aspects Related to Sterilization and Its Effect on the Rotary Instruments

Endodontic Nickel-titanium (Ni-Ti) files were used for root canal treatment for more than 25 years because of their flexibility, flexural, and torsional resistance [20]. Many studies have been done observing the effects of sterilization on these instruments’ properties. Some of them found no significant effects [21]. Condorelli et al. [22] identified the same type of increased resistance to cyclic fatigue, although the thermal applications did not alter instrument surface morphology  but resulted in significant changes in the instrument bulk with the appearance of an R-phase and improved fatigue resistance. Sonntag and Peters [6] found a better fatigue life after five cycles of dry-heat sterilization at 180ºC.

Conversely, many studies found sterilization negatively impacting the file’s life span, features, characteristics, and properties [23-27]. Autoclaving and re-using of the endodontic files more than three times can lead to a change in the physical properties of the alloy, like blunt cutting edge, pitting chipping, and fritting [28]. Another study has confirmed that multiple or a single autoclave cycle of endodontic files can result in the file’s surface corrosion with a reduction of flexural and torsional fatigue resistance [29].

Most of the studies proved that cyclic fatigue resistance decreased and led to a high chance of file fracture especially when the root canal curvature increased [25,26,27].

Aspects Related to Corrosion and Its Effect on the Rotary Instruments

It is well documented that bacterial infection of the root canal is the primary cause of apical periodontitis [8,30,31]. The apical periodontitis is the result of bacterial invasion and consecutive colonization of the entire endodontic system. Thus treatment has to be directed toward the elimination of micro-organisms from within the endodontic system and prevention of re-infection [31]. Therefore, chemo- mechanical preparation of the root canal, which is a combination of mechanical instrumentation and antibacterial irrigation, is the critical stage in canal disinfection. These irrigants are also used to suspend and rinse away debris created during instrumentation, dissolve the organic tissue, or as a lubricant for instruments, to remove the smear layer.

Since there is obvious evidence that autoclave and chemical sterilisation technique goes the best hand in  hand  for  re-used  dental files and burs, causing a 100% microbial elimination [32], files corrosion has to be assessed as well. Rutala and Weber [33] demonstrated the proper decontamination steps of endodontic files with chemical agents by using Sodium hydroxide (NaOH) solution for 24 hours, 1 hour respectively, then using guanidine thiocyanate for 24 hours, 1 hour and 15 minutes respectively. Later on, they sterilised files by autoclave at 134oC for 18 minutes. Also, a short decontamination process by immersing the files with chlorhexidine solution, manual cleaning then submersion in 1% NaOCl solution, ultrasonic cleaning, and finally steam sterilising by autoclave was advocated [33].

It was shown that during extended periods in NaOCl solutions, corrosion may be enhanced [34] or minimized depending on the pH of the environment [35]. Though the impact of NaOCl did not show any difference in the cutting efficiency or resistance to fracture of Ni-Ti instruments [36,37], it did result in reduced resistance to cyclic fatigue [38,39] and the presence of corrosion [6]. Further studies in which the percentage of NaOCl was low (1%) showed no major impact on Ni-Ti instruments; however, those that studied the impact of a 5% solution noted significant changes [40]. Some studies showed that a sterilization cycle along with immersion in NaOCl did not result in any substantial instrument changes [41]. In Catania University of Italy [42], the authors conducted a study to show the effect of treating files with either 5% NaOCl, sterilisation or heat-sterilized Ni-Ti rotary files or both and whether there was an effect on the cyclic fatigue resistance
or not. They have collected 210 files, which were twisted files (TF) (SybronEndo, Orange, CA) and Hyflex CM (Coltene Whaledent, Cuyahoga Falls, OH) files size 25/0.06. They were divided into 7 groups, the first group was not sterilised by autoclave or immersed with NaOCl, group 2 and 3 did not autoclave files, but immersed them with 5% of NaOCl once and three times respectively, Group 4 and 5 files were only autoclaved once and three times without immersion into 5% NaOCl, while group 6 and 7 treated with both 5% NaOCl and autoclave once and three times respectively. The files were then tested using field-emission scanning electron microscopy and x-ray energy-dispersive spectrometric (EDS) analysis to determine file surface defects and fractures. TF showed lower fatigue resistance than CM files group after 3 times autoclave sterilisation. EDS showed that immersion of Hyflex CM files in 5 % NaOCl developed an oxide-rich layer on the file’s external surfaces. EDS also showed that repeatedly treating files with sterilisation or chemical cycles (NaOCl 5%) has no morphological changes on the CM files surface apart from TF files that have demonstrated low flexural resistance with an increased chance of fracture.

Aspects Related to Mechanical Failure

“A material will fail by torsion when the ultimate shear strength is exceeded” according to Walia [43]. Studies proved that an instrument will fracture if its ultimate strength is exceeded [44-47] or if a fracture line has extended to such an extent that the remaining intact cross- section of the file is unable to bear the functional load [48] thus complicating the whole treatment. Scanning electron microscopy observations proved that  instruments  deteriorate  while  in  use,  and develop defects and cracks on their surfaces inducing fracture propagation [3,28,49,50]. Although new instruments can fracture at their first canal use, those that are used for three or more canals may have a higher susceptibility for fracture. Gambarini [51] demonstrated that the used instruments had a lower resistance to fracture than new ones.

There are 2 possible mechanisms of fracture described in the literature:

a) Torsional or sheer fatigue. The fractographic image of shear failure is very spectacular, showing the plastic deformation of the flutes adjacent to the fracture site, along with concentric circular markings at the periphery with a ‘fibrous’ appearance in the center. The fibrous region corresponds to the microscopic dimples in high power, while the circular markings are due to abrasion of the opposing surfaces on either side of the fracture [52-56].

b) Cyclic fatigue. The term ‘cyclic fatigue’ has been used to describe the breakage of Ni-Ti instruments after continuous rotation in a curved canal. An instrument rotating with curvature is effectively subjected to a completely reversed cyclic loading at its surface. A form of fatigue loading, such rotational bending has been implicated as the reason for breakage of some 44–91% of Ni-Ti engine-files fractured clinically [52,53,55,56].

It has been emphasised that there is no fracture caused by purely one of the mechanisms, there is always a combined effect of the two. Frequent reuse of endodontic files can lead to change in their physical properties and cause file fracture particularly in curved and calcified canals [27]. Some reports found that the incidence of separation of unused rotary Ni-Ti files is about 1% [57-62] while distortion was noticed to occur in up to 60% of the instruments used [63], but it is estimated that the incidence of instrument fracture in instruments used multiple times varies between 0.39% and 21% [44,46,47,50,64- 66]. There are also reports that Ni-Ti engine-files may fracture without any warning signs [53,54,57].

Conclusion

For the high standard of dental care, it is mandatory to segregate single-use endodontic instruments like files and reamers according  to the department of health policy nevertheless, steam sterilisation   is essential to instruments that cannot be segregated like endodontic rulers, dental hand instruments, rubber dam clamps or handpieces. Furthermore, proper infection control and to obtain a healthy environment for patients and dental staff. Ni-Ti files are the most commonly used endodontic files in dentistry as they have a good shape memory with low risk of fatigue, in addition to that they are safe, easy to use, and discard [22]. The dental clinicians should have full knowledge and appropriate diagnosis about prion disease, its way of transmission, proper decontamination, and how to prevent    it even if there is no clear confirmation of its transmition by means of dental procedures. The high binding capacity of Prion protein to dental metal instrument surfaces can render disinfection very difficult and challenging, hence sterilisation methods can be a very big task to perform. Judging by mechanical point of view, the reuse of a rotary file, no matter the alloy it’s been made of and the stress it is capable to bare, is risky and might jeopardise the treatment itself along with its outcome. Using  rotary files as single-use instruments can lead    to increased clinical confidence and a positive outcome of dental treatment.

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Convalescent Plasma Therapy for COVID-19

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DOI: 10.31038/CST.2020532

Introduction

A novel flu-like coronavirus emerged from Wuhan, China in December 2019. It was named Severe Acute Respiratory Syndrome Coronavirus 2, (SARS-CoV-2), and causes Coronavirus Disease 2019, (COVID-19) [1]. SARS-CoV-2 rapidly spread, and on March 11th, 2020, the WHO declared COVID-19 a pandemic [2]. As of July 3rd there have been 10,719,946 confirmed cases of COVID-19 worldwide, including 517,337 deaths, reported to the World Health Organization [3]. Many therapies are being investigated for their anti-viral or immune modulation properties to treat COVID-19, with efficacy so far being demonstrated for dexamethasone [4] and remdesivir [5]. In recent pandemics, no standardized treatments were identified for SARS-CoV-1, Middle East Respiratory Syndrome or Ebola, due to the limited number of controlled clinical trials undertaken at the time, with none performed on SARS-CoV-1, and only 3 and 11 for Middle East Respiratory Syndrome and Ebola, respectively [6]. However, this has been addressed for COVID-19, and there are currently 1,358 clinical trials registered with ClinicalTrials.gov, of which 209 are investigating the use of convalescent plasma to treat COVD-19 [7].

Principles of Convalescent Plasma

Convalescent plasma is plasma, obtained from patients who have recovered from an infectious disease such as COVID-19, which contains antibodies specific to the pathogen, in this case SARS-CoV-2. This passive immunotherapy works by neutralizing pathogens, thereby decreasing the likelihood of cytokine storm occurring in the recipients. Convalescent plasma has been used as a therapeutic agent for over a hundred years. One of its earliest interventions for treating viral diseases was the Spanish H1N1 influenza A in 1918. Since then it has been used to treat Avian H5N1 influenza A epidemic (2003), Severe Acute Respiratory Syndrome (SARS, SARS-CoV-1) epidemic (2003), H1N1 influenza pandemic (2009-10), Middle East Respiratory Syndrome (MERS-CoV) epidemic (2012), Chikungunya, Ebola epidemic (2014-16) and Zika [2,3].

Is Convalescent Plasma Efficacious?

While it is important to await the findings for the clinical trials, there is some evidence that this approach will be successful. A meta- analysis of 32 papers evaluating the efficacy of convalescent plasma in SARS Coronavirus patients, (699 treated versus 568 untreated controls), demonstrated a reduced mortality rate in the plasma arm, compared with placebo or no treatment (odds ratio: 0.25%; 95% CI: 0.14-0.45). However, many studies included in the meta-analysis were of poor quality, lacked control groups, and demonstrated moderate or high risk of bias [8]. A meta-analysis of the use of convalescent plasma in Spanish flu also demonstrated a reduced mortality rate [9]. There is some evidence about the efficacy of convalescent plasma from several uncontrolled case series of convalescent plasma use in COVID-19 patients. A case-series of 5 critically ill COVID-19 patients, aged 36-65 years, received convalescent plasma, with a SARS-CoV-2 specific IgG binding titre greater than 1:1000 and a neutralization titre greater than 40, on days 10-22 following admission. The results were encouraging, with normalization of body temperature occurring within 3 days in 4 of the 5 patients. In addition, viral loads decreased and acute respiratory distress syndrome also resolved in 4 patients, both within 12 days of the transfusion, and 3 patients no longer required ventilation within 3 weeks [10]. Duan et al. 2020 also reported an improvement in 10 severely affected patients who received convalescent plasma [11]. Viremia disappeared within 7 days, due to significantly increased or maintained high levels of neutralizing antibody. In addition, lymphocyte counts increased and C-reactive protein values decreased, in comparison to the pre-transfusion levels. There were also varying levels of adsorption of lung lesions.

Zhang et al. 2020 reported the outcomes in 4 critically ill COVID-19 patients, who received various quantities of convalescent plasma, (300, 400 and 2,400ml) [12]. All patients became RT-PCR negative within 3-22 days of receiving the transfusion. However, the contribution from other therapeutic agents administered could not be discerned. A retrospective, observational study involving a small number of participants was less promising. Despite, all 6 patients testing negative for SARS-CoV-2 RNA within 3 days of receiving the transfusion, 5 of them subsequently died. However, the patients who received plasma survived significantly longer than the control arm. The median day of transfusion was 21.5, and it was postulated this was too late to minimise the hyperimmune response, as the 1 patient who received treatment on day 11 survived [13]. Kong et al. 2020 reported a case of a centenarian, who demonstrated improved clinical and laboratory findings following 2 transfusions of convalescent plasma, and was successfully treated by this approach [14]. In the study by Ahn et al. 2020, 2 COVID-19 patients who presented with severe pneumonia and acute respiratory distress syndrome demonstrated improved oxygenation, and decreased viremia and inflammatory markers, after the use of methylprednisolone and convalescent plasma [15].

A systematic review of five studies evaluating convalescent plasma in COVID-19 patients demonstrated a reduced mortality rate in critically ill patients. In the majority of cases, an increase in the neutralizing antibody titres was apparent, alongside disappearance of SARS-CoV-2 RNA, and an improvement in clinical symptoms. This study concluded that convalescent plasma was an effective means of reducing mortality in COVID-19 [16]. A Cochrane Rapid Review by Valk et al. 2020 included 32 patients, from seven case-series and one prospectively planned study [17]. Valk et al. 2020 reported a high level of bias, due to the small numbers of participants, study design, different disease severities and varying treatments of the patients [17]. They were unable to perform any statistical analysis and deemed very low-certainty evidence for efficacy, with the data available at present [17]. The first randomized clinical trial evaluating convalescent plasma was performed in Wuhan, China. It recruited 103 participants with severe or life-threatening COVID-19 and compared convalescent plasma in addition to standard treatment (n = 52) to standard treatment alone (control) (n = 51). However, no statistical significant benefit in mortality or clinical improvement 28 days after the plasma transfusion in all randomized patients was observed [18]. However, a possible benefit was seen in the severely ill subgroup, but not the critically-ill group, when the data was reanalysed according to disease severity. The lack of statistical significance was thought to arise from the early termination of the trial, due to enrolment difficulties as the virus was being contained. This resulted in only 103 of the expected 200 cases being recruited, which subsequently underpowered the trial [18].

Safety of Convalescent Plasma

So far the safety data for this treatment seems promising, despite concerns that antibody-mediated enhancement may exacerbate the condition via a proinflammatory effect, or complications may arise from transfusion-related lung injury and transfusion-related circulatory overload [19]. Other potential adverse events include breathing difficulties, transfusion transmitted infection, and hypersensitivity reactions, which manifest as rash, fever or chills. No severe adverse events were reported by Ahn et al. 2020 (n=2), Duan et al. 2020 (n=10), Olivares-Gazca et al. 2020 (n=10), Salazar et al. 2020 (n=25), Zhang et al. 2020 (n=4) or Zeng et al. 2020 (n=6) [11-13,15,20,21], and the meta-analysis also confirmed it was safe (Rajendran et al. 2020) [16], whereas Valk et al. 2020 reported very low- certainty evidence of adverse events [17]. In the trial by Li et al. 2020 [18], two of 52 recipients of convalescent plasma experienced adverse events within hours of receiving the transfusion. The chills and rash manifest in one of those patients suggested a transfusion reaction. The adverse events in both cases were managed by corticosteroids [18,22].

What do We Need to Know?

The controlled trials evaluating convalescent plasma will provide important information on the optimal dose and time to treat patients, donor selection, plasma collection and which patients are most likely to benefit. The meta-analysis on the use of convalescent plasma to treat Spanish flu by Luke et al. 2006 suggested that early treatment, (after < 4 days of pneumonia complications), resulted in improved mortality rates than late treatment, (after ≥ 4 days of pneumonia complications), which was similar to the mortality rate among controls [9]. The study by Zeng et al. 2020 supports the use of convalescent plasma as an early intervention [13], and also by Li et al. 2020, particularly in less severely ill patients [18]. The concentration of donor neutralizing antibodies is likely to affect the efficacy, and these levels can be influenced by the prior treatment of the donor, such as steroids, antiviral drugs and intravenous immunoglobulin. It will also be interesting to explore convalescent plasma in combination with antiviral agents, such as remdisivir, due to their different mechanisms of action [22]. There is previous evidence that they may work well together [23]. The results of the many clinical trials investigating the use of convalescent plasma in COVID-19 are eagerly awaited, but the data from case-series and the use of this treatment in previous infectious diseases appears promising.

Keywords

Convalescent plasma, Coronavirus disease 2019, COVID-19, Passive immunotherapy, SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2

References

  1. Peeri NC, Shrestha N, Rahman MS, Zaki R, Tan Z, et al. (2020) The SARS, MERS and novel coronavirus (COVID-19) epidemics, the newest and biggest global health threats: what lessons have we learned? International Journal of Epidemiology.
  2. Franchini M (2020) Why should we use convalescent plasma for COVID-19? European Journal of Internal Medicine 77: 150-151. [crossref]
  3. Wong HK, Lee CK (2020) Pivotal role of convalescent plasma in managing emerging infectious diseases. Vox sanguinis World Health Organization Coronavirus Disease (COVID-19) Dashboard https://covid19.who.int/ [crossref]
  4. Mahase E (2020) Covid-19: Low dose steroid cuts death in ventilated patients by one third, trial finds. BMJ 369: m2422. [crossref]
  5. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, et al. (2020) Remdesivir for the Treatment of Covid-19 – Preliminary Report. The New England journal of medicine NEJMoa2007764. [crossref]
  6. Body R and Felton T (2020) MAHSC Seminar Series COVID-19 – Current & future diagnostic and therapeutic approaches, 2nd July https://www.youtube.com/ watch?v=oapbjes0es4
  7. ClinicalTrials.gov https://clinicaltrials.gov/ NIH US National Library of Medicine Accessed 03/07/2020
  8. Mair-Jenkins J, Saavedra-Campos M, Baillie JK, Cleary P, Khaw FM, et al. (2015) The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. The Journal of Infectious Diseases 211: 80-90. [crossref]
  9. Luke TC, Kilbane EM, Jackson JL, Hoffman SL (2006) Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment? Annals of Internal Medicine 145: 599-609. [crossref]
  10. Shen C, Wang Z, Zhao F, Yang Y, Li J, et al. (2020) Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA 323: 1582-1589. [crossref]
  11. Duan K, Liu B, Li C, Zhang H, Yu T, et al. (2020) Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proceedings of the National Academy of Sciences of the United States of America 117: 9490-9496. [crossref]
  12. Zhang B, Liu S, Tan T, Huang W, Dong Y, et al. (2020) Treatment with Convalescent Plasma for Critically Ill Patients with Severe Acute Respiratory Syndrome Coronavirus 2 Infection. Chest 158: e9-e13. [crossref]
  13. Zeng QL, Yu ZJ, Gou JJ, Li GM, Ma SH, et al. (2020) Effect of Convalescent Plasma Therapy on Viral Shedding and Survival in Patients with Coronavirus Disease 2019. The Journal of Infectious Diseases 222: 38-43. [crossref]
  14. Kong Y, Cai C, Ling L, Zeng L, Wu M, et al. (2020) Successful treatment of a centenarian with coronavirus disease 2019 (COVID-19) using convalescent plasma. Transfusion and Apheresis Science 102820. [crossref]
  15. Ahn JY, Sohn Y, Lee SH, Cho Y, Hyun JH, et al. (2020) Use of Convalescent Plasma Therapy in Two COVID-19 Patients with Acute Respiratory Distress Syndrome in Korea. Journal of Korean Medical Science 35: e149. [crossref]
  16. Rajendran K, Krishnasamy N, Rangarajan J, Rathinam J, Natarajan M, et al. (2020) Convalescent plasma transfusion for the treatment of COVID-19: Systematic review. J Med Virol. [crossref]
  17. Valk SJ, Piechotta V, Chai KL, Doree C, Monsef I, et al. (2020) Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a rapid review. The Cochrane Database of Systematic Reviews 5: CD013600. [crossref]
  18. Li L, Zhang W, Hu Y, Tong X, Zheng S, et al. (2020) Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life- threatening COVID-19: A Randomized Clinical Trial. JAMA e2010044. [crossref]
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  20. Olivares-Gazca JC, Priesca-Marín JM, Ojeda-Laguna M, Garces-Eisele J, Soto- Olvera S, et al. (2020) Infusion of convalescent plasma is associated with clinical improvement in critically ill patients with COVID-19: A pilot study. Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion 72: 159- 164.
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  22. Casadevall A, Joyner MJ, Pirofski L (2020) A Randomized Trial of Convalescent Plasma for COVID-19—Potentially Hopeful Signals. JAMA. [crossref]
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Latent Genital Tuberculosis – A Possible Explanation for Unexplained Infertility

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DOI: 10.31038/IGOJ.2020321

Abstract

Latent Genital Tuberculosis (LGTB) is commonly asymptomatic, and it is usually diagnosed during infertility investigations. The main objective of the present study was to establish the role of LGTB in causing unexplained infertility.

Material and method: 517 women, from January 2016- December 2018, at Calcutta Fertility Mission, had undergone DNA-PCR test (polymerase chain reaction) for screening of LGTB, then had had subsequent treatment with Anti-Tubercular Drugs (ATD) with or without laparoscopy. These patients were further classified as Group A and Group B based on their findings on laparoscopy to have early endometriosis or minor tubal defects or both. The Clinical pregnancy rate was calculated and analyzed among groups of women who were treated with ATD; treated with ATD and laparoscopy and those who were treated with estrogen-progestins for endometriosis.

Result: 28.6% of patients with apparently unexplained infertility were found to have LGTB and 31.76% of them had conceived following treatment with ATD. 71.4% of the patients who did not have LGTB had to be re-evaluated by laparoscopy. 35.64% patients in Group A and 34.15% patients in Group B, were diagnosed to have early endometriosis. Minor tubal defects on laparoscopy were found in as high as 43.56% of Group A patients and 29% in Group B. Hence the patients in Group A who had LGTB and had to be treated with ATD were seen to have quite higher prevalence of tubal defects compared to Group B and it has been seen to be statistically significant also (p value=0.003). 36.36% of Group A patients had conceived within 6 months of laparoscopy and 23.36% of women in Group B had achieved pregnancy.

Conclusion: LGTB is one of the major causes of apparently unexplained infertility and even the factors like early endometriosis or minor tubal defects are often associated with this condition and enhances the ill-effect causing infertility.

Keywords

Latent genital tuberculosis, Unexplained infertility, Laparoscopy, Pregnancy, Endometriosis, Tubal defect

Introduction

Unexplained infertility which amounts to about 30% of the infertile couple, can be defined as the lack of an obvious cause for a couple’s infertility and the inability to conceive after at least 12 cycles of unprotected intercourse for whom all the standard evaluations are normal. The veracity of ‘unexplained infertility’ term has been challenged by many clinicians and researchers and it has been emphasized that the assignment of the title to an infertile couple is much dependent on the quality and nature of the diagnostic tests performed [1,2]. According to the NICE  guidelines,  necessary  tests for unexplained infertility are semen analysis, assessment of ovulation and the luteal phase, and assessment of tubal patency by hysterosalpingogram or laparoscopy. However, there is controversy about the value of endometrial biopsy, ovarian reserve (Serum anti- mullerian hormone, antral follicle count), post-coital test and serum prolactin levels. The inability to find the specific cause of couples’ infertility does not mean that there is absolutely no cause for the disorder. Factors including lack of strong evidence, couples’ impatience for completion of standard protocols and dominance of Artificial Reproductive Technique (ART) treatment compared to other options in infertility clinics lead to diversity of clinical practice regarding unexplained infertility. Extensive research should be conducted on other possible causes of failed conception such as ovarian and testicular dysfunctions, sperm and oocyte quality, minor fallopian tube defects, endometrial receptivity, implantation failure and endometriosis [3,4]. Latent Genital Tuberculosis (LGTB) is a major health problem in many developing countries in Asia and Africa and has been proved to be responsible for a significant proportion of female infertility. It is asymptomatic in majority of the affected women and is diagnosed only during infertility work-up [5]. The most involved genital organs (whether solely or with other organs) have been seen to be fallopian tubes (63.84%), ovaries (46.15%), endometrium (38.46%) and the cervix (23.07%) in female genital tuberculosis but the involvement has not been documented in LGTB [6]. However, a few authors have reported the endometrium to be involved the most with as high as 60% in cases of infertility [7]. The present study was conducted to determine the role of latent genital tuberculosis in couples diagnosed with apparently unexplained infertility.

Material and Methods

This retrospective study was conducted at Calcutta Fertility Mission in Kolkata, India, from January 2016 to December 2018. The data were collected from a total of 517 patients as cases between 25-35 years of age, who had primary infertility which was apparently unexplained. These patients had normal ovulatory function and normal ovarian reserve, fallopian tubes appeared normal on hysterosalpingogram, their partners had normal semen parameters. They had undergone routine tests along with the DNA-PCR test with an endometrial aspirate on day 21 to day 24 of respective menstrual cycles (Table 1).

Table 1: Age of patients in groups.

 

Age

Total

p Value

Significance

25-30

31-35

PCR

POSITIVE

58 (29.74)

90 (27.95)

148 (28.63)

0.662

Not Significant

NEGATIVE

137 (70.26)

232 (72.05)

369 (71.37)

Total

195 (100)

322 (100)

517 (100)

 

 

Group A and B

Mild/Moderate Endometriosis

59 (33.52)

103 (35.03)

162 (34.47)

0.426

Not Significant

Tubal Defects

52 (29.55)

99 (33.67)

151 (32.13)

Both

65 (36.93)

92 (31.29)

157 (33.4)

Total

176 (100)

294 (100)

470 (100)

 

 

Pearson’s Chi Square test for Independence of Attributes.

517 patients were grouped initially as those who had LGTB (PCR positive) and who did not have LGTB (PCR negative). 148 (28.6%) patients were found to have LGTB and 369 (71.4%) of them were not affected (Table 2). These 148 patients were treated with Anti- tubercular drugs (ATD) for 6 months and subsequently 47 (31.76%) of them had conceived following the treatment.

Table 2: Patients of unexplained infertility with LGTB.

PCR

Frequency

Percent

Positive

148

28.6

Negative

369

71.4

Total

517

100.0

Hence in the said cohort there were 101 patients who could not conceive after being treated with ATD and 369 patients were PCR negative and had to be further re-evaluated for infertility. These women were grouped as Group A (101) (PCR negative after treatment with ATD) and Group B (369) (PCR negative). These patients were counselled for laparoscopy and based on the laparoscopy findings they were diagnosed to have either Stage 1 or Stage 2 endometriosis, or minor tubal defects and some had both early endometriosis and minor tubal defect.

On laparoscopy these patients with early endometriosis had one or two of the following features:

1. Endometriotic spots on pelvic organs and in POD

2. Flimsy adhesions in POD.

3. Pseudocavitations.

4. Peritoneal deficiency.

These patients were treated with estrogen and progesterone combination or with dienogest for 3-6 months for endometriosis and patients with minor tubal defects were corrected by laparoscopy. The post-treatment Clinical Pregnancy Rates (CPR) were calculated and analysed in all these groups (Table 3).

Table 3: Clinical Pregnancy in patients in Group A and B.

Clinical pregnancy

Group

Total

p Value

Significance

Mild/Moderate Endometriosis

Tubal Defects

Both

Group A

Pregnancy

No

26 (72.22)

28 (63.64)

16 (76.19)

70 (69.31)

0.528

Not Significant

Yes

10 (27.78)

16 (36.36)

5 (23.81)

31 (30.69)

Total

36 (100)

44 (100)

21 (100)

101 (100)

 

 

Group B

Pregnancy

No

94 (74.6)

82 (76.64)

108 (79.41)

284 (76.96)

0.650

Not Significant

Yes

32 (25.4)

25 (23.36)

28 (20.59)

85 (23.04)

Total

126 (100)

107 (100)

136 (100)

369 (100)

 

 

Pearson’s Chi Square test for Independence of Attributes.

Statistical Analysis

Categorical variables will be expressed as Number of patients and percentage of patients and compared across the 2 groups Pearson’s Chi Square test for Independence of Attributes. The statistical software SPSS version 20 will be used for the analysis. An alpha level of 5% has been taken, i.e. if any p value is less than 0.05 it will be considered as significant.

Ethical Consideration

The Ethical Committee of Calcutta Fertility Mission has given clearance for the retrospective study of a prospective database on 21/10/2019 (CFM/2019/029). Written informed consent has been obtained from all women who participated in the study.

Discussion

Management of infertile couples should always be individualized. The key variables like age, treatment history, costs and risks should be considered in selecting treatment plan of every couple. Over recent decades, the use of medically assisted reproduction (MAR) has increased enormously [8]. It is important to select couples who would actually benefit from MAR [9,10]. In couples with unexplained infertility the chance of a natural conception within 1 year is 30% or higher. MAR is no better than tailored expectant management (TEM) of 6–12 months, except in those who have gradually diminishing ovarian reserve [11,12]. Most often TEM is underutilised either due to failure in identifying couples who are eligible for TEM, or couples do not undergo expectant management for lack of advice by medical professional or impatience of the couple concerned.

Latent genital tuberculosis is rare in developed countries but is an important cause of subclinical chronic pelvic inflammatory disease and infertility in underdeveloped and developing countries. Previous literature show genital tuberculosis as a cause of infertility in 3-16% of women, varying to about 20% in India [13,14]. In the present study 28.6% of patients with apparently unexplained infertility were found to have LGTB and 31.76% of them had conceived following treatment with ATD. 71.4% of the patients who did not have LGTB had to be re-evaluated by laparoscopy along with those who could not achieve pregnancy even after treatment with ATD.

The relationship between endometriosis and infertility has been debated since years. Women with endometriosis tend to have a 2-10% lower monthly fecundity [15,16]. 25-50% infertile women are likely to have endometriosis which results in about 6-8% of the total population [17]. Several mechanisms have been proposed to explain the association between endometriosis and infertility which include distorted pelvic anatomy, endocrine and ovulatory abnormalities and altered humoral and cell-mediated functions in the endometrium. Major pelvic adhesions or peritubal adhesions that alter the tubo-ovarian relation, impair oocyte release from the ovary, inhibit ovum pickup, or impede ovum transport [18]. In our study 35.64% patients with unexplained infertility in Group A and 34.15% patients in Group B, were diagnosed to have early endometriosis. (Stage I and II).The overall prevalence of endometriosis in population‐based studies varies from 0.8% to 6%; however, in case of associated infertility, the prevalence seems to be considerably higher, ranging from 20% to 50%, but with significant variation over time periods and the age of patients [19-22].

In our previous study it has been stated that 846 out of 1726 (49%) women with unexplained infertility, were diagnosed to have minor tubal defects and were treated for the same by laparoscopy. The clinical pregnancy rate was about 27% following the treatment [23].

Similarly in the present study, we had detected minor tubal defects on laparoscopy in as high as 43.56% of Group A patients and 29% in Group B. Hence the patients in Group A who had LGTB and had to be treated with ATD were seen to have quite higher prevalence of tubal defects compared to Group B and it has been seen to be statistically significant also (p value=0.003). 36.36% of Group A patients had conceived within 6 months of laparoscopy and 23.36% of women in Group B had achieved pregnancy.

In the present study we had also found 20.79% women in Group A and 36.86% in Group B had both minor tubal defects and early endometriosis. Early endometriosis, minor tubal defects or even both of these conditions have been seen to be associated with a substantial number of patients with apparently “unexplained” infertility. A strong association of LGTB has been noticed with these factors also. All these etiological factors have been found to be statistically significant in Group A and Group B (p value=0.003) (Table 4).

Table 4: Other etiology of infertility in Group A and B.

Group A

Group B

Total

p Value

Significance

Etiology

Mild/Moderate Endometriosis

36 (35.64)

126 (34.15)

162 (34.47)

0.003

Significant

Tubal Defects

44 (43.56)

107 (29)

151 (32.13)

Both

21 (20.79)

136 (36.86)

157 (33.4)

Total

101 (100)

369 (100)

470 (100)

 

 

Pearson’s Chi Square test for Independence of Attributes.

Our patients with early endometriosis were treated with estrogen- progestins or with dienogest for 6 months primarily and none of them required surgical intervention. 27.78% women in Group A and 25.4% in Group B had conceived after the treatment and ovulation induction.

Estrogen-progestins with the lowest possible estrogen  dose should be chosen to combine optimal lesion suppression and thrombotic risk limitation. Progestins should be suggested in women who do not respond or manifest intolerance to estrogen-progestins [24]. According to Kitirat Techatraisak et al. dienogest has been seen to substantially improve endometriosis-associated symptoms such as debilitating chronic pelvic pain, and consequently, health-related quality of life [25]. Jacobson et al. in their study had shown laparoscopic resection or ablation of minimal and mild endometriosis enhances fecundity in infertile women [26].

After treatment of LGTB, early endometriosis and correction of minor tubal defects, 23.81% patients had spontaneous conception    in Group A and 20.59% of women in Group B had conceived after treatment of endometriosis and laparoscopy.

Conclusion

From the present study we can say that LGTB has a very important role in unexplained infertility and once detected and treated it can even yield spontaneous pregnancy. Persistence of infertility even after the treatment of LGTB, may be due to other associated problems like early endometriosis, minor tubal defects or both, which have also been in patients who did not have LGTB. These were undetected until they had undergone laparoscopy. There is strong possibility that presence of LGTB aggravates these conditions.

Acknowledgment

Mr. Souvik Dutta for management, analysis and interpretation of the data and Ms. Orphi Bhattacharya for preparation of manuscript.

Abbreviations: LGTB: Latent Genital Tuberculosis; ATD: Anti-Tubercular Drugs

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