Effect of Combination Therapy of Hydroxychloroquine and Azithromycin on Mortality in Patients With COVID‐19

Conflicting evidence regarding the use of hydroxychloroquine (HCQ) and azithromycin for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection do exist. We performed a retrospective single‐center cohort study including 377 consecutive patients admitted for pneumonia related to coronavirus disease 2019 (COVID‐19). Of these, 297 were in combination treatment, 17 were on HCQ alone, and 63 did not receive either of these 2 drugs because of contraindications. The primary end point was in‐hospital death. Mean age was 71.8 ± 13.4 years and 34.2% were women. We recorded 146 deaths: 35 in no treatment, 7 in HCQ treatment group, and 102 in HCQ + azithromycin treatment group (log rank test for Kaplan–Meier curve P < 0.001). At multivariable Cox proportional hazard regression analysis, age (hazard ratio (HR) 1.057, 95% confidence interval (CI) 1.035–1.079, P < 0.001), mechanical ventilation/continuous positive airway pressure (HR 2.726, 95% CI 1.823–4.074, P < 0.001), and C reactive protein above the median (HR 2.191, 95% CI 1.479–3.246, P < 0.001) were directly associated with death, whereas use of HCQ + azithromycin (vs. no treatment; HR 0.265, 95% CI 0.171–0.412, P < 0.001) was inversely associated. In this study, we found a reduced in‐hospital mortality in patients treated with a combination of HCQ and azithromycin after adjustment for comorbidities. A large randomized trial is necessary to confirm these findings.

The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection is spreading worldwide since December 2019 and still no proven effective therapy has been found. First therapy proposed to treat coronavirus disease 2019 (COVID‐19) has been the association of lopinavir‐ritonavir, a protease inhibitor approved for HIV infection. However, Cao et al. observed no benefit comparing lopinavir‐ritonavir treatment of hospitalized patients with severe COVID‐19, ¹ and this treatment is currently not recommended. Currently, only remdesivir has been approved for COVID‐19 treatment, as it reduced recovery time by 4 days in 1,063 patients randomized to either remdesivir 200 mg loading dose followed by 100 mg daily or placebo for up to 10 days ² with a similar rate of adverse events between the 2 groups. ³ However, no effect on in‐hospital mortality was found.Chloroquine and its derivative hydroxychloroquine (HCQ), based on few preclinical studies, have also been proposed as therapies for COVID‐19. A Chinese randomized trial in patients with mild disease showed a significantly shorter recovery time in the group treated with HCQ vs. the standard of care along with a radiological improvement. ⁴ Differently, a retrospective study performed in the United States Veterans Health Administration medical centers found an increased mortality associated with the treatment with HCQ. ⁵ Moreover, an observational study has shown no significant association between HCQ use and risk of intubation or death. ⁶ Furthermore, a recent randomized controlled trial has found no differences between patients treated with HCQ plus the standard of care vs. the standard of care alone in terms of virus elimination. ⁷ On the basis of a very small nonrandomized study, azithromycin has been proposed as possible treatment in association with HCQ. ⁸ Azithromycin, is an antibiotic belonging to the class of macrolides, with some proven efficacy in acute respiratory distress syndrome. ⁹ , ¹⁰ It is known to have immunomodulatory properties through the polarization of macrophages toward the reparative state ¹¹ and the reduction in the production of pro‐inflammatory cytokines, such as IL‐8, IL‐6, TNF alpha, ¹² and iNOS expression. ¹³ Recently, two large retrospective studies evaluating in‐hospital mortality associated with the use of the combination of HCQ and azithromycin (or another macrolide, such as clarithromycin), have shown no benefits. ¹⁴ Despite the lack of a proven clinical efficacy and some concerns regarding the possible QT prolongations caused by the association of HCQ and azithromycin, ¹⁵ given the low price and the wide availability, the association of these two drugs has become the most used treatment in patients with moderate‐severe COVID‐19.Because of the urgent need to find answers to the many questions posed by the fight to SARS‐CoV2 infection and some negative evidences regarding the use of HCQ, we here propose a retrospective observational study to assess the efficacy of the combination of HCQ plus azithromycin for hospitalized patients with medium‐severe COVID‐19.     

Melatonin reduces hepatic mitochondrial dysfunction in diabetic obese rats

Hepatic mitochondrial dysfunction is thought to play a role in the development of liver steatosis and insulin resistance, which are both common characteristics of obesity and type 2 diabetes mellitus (T2DM). It was hypothesized that the antioxidant properties of melatonin could potentially improve the impaired functions of hepatic mitochondria in diabetic obese animals. Male Zucker diabetic fatty (ZDF) rats and lean littermates (ZL) were given either melatonin (10 mg/kg BW/day) orally for 6 wk (M‐ZDF and M‐ZL) or vehicle as control groups (C‐ZDF and C‐ZL). Hepatic function was evaluated by measurement of serum alanine transaminase and aspartate transaminase levels, liver histopathology and electron microscopy, and hepatic mitochondrial functions. Several impaired functions of hepatic mitochondria were observed in C‐ZDF in comparison with C‐ZL rats. Melatonin treatment to ZDF rats decreases serum levels of ALT (P < 0.001), alleviates liver steatosis and vacuolation, and also mitigates diabetic‐induced mitochondrial abnormalities, glycogen, and lipid accumulation. Melatonin improves mitochondrial dysfunction in M‐ZDF rats by increasing activities of mitochondrial citrate synthase (P < 0.001) and complex IV of electron transfer chain (P < 0.05) and enhances state 3 respiration (P < 0.001), respiratory control index (RCR) (P < 0.01), and phosphorylation coefficient (ADP/O ratio) (P < 0.05). Also melatonin augments ATP production (P < 0.05) and diminishes uncoupling protein 2 levels (P < 0.001). These results demonstrate that chronic oral melatonin reduces liver steatosis and mitochondria dysfunction in ZDF rats. Therefore, it may be beneficial in the treatment of diabesity.     

Update on the use of dapsone in dermatology

Dapsone (4,4'-diaminodiphenylsulfone) is the only remaining sulfone used in anthropoid therapeutics and is commercially available as an oral formulation, an inhaled preparation, and a 5% or 7.5% cream. Dapsone has antimicrobial effects stemming from its sulfonamide-like ability to inhibit the synthesis of dihydrofolic acid. It also has anti-inflammatory properties such as inhibiting the production of reactive oxygen species, reducing the effect of eosinophil peroxidase on mast cells and down-regulating neutrophil-mediated inflammatory responses. This allows for its use in the treatment of a wide variety of inflammatory and infectious skin conditions. Currently in dermatology, the US Food and Drug Administration (FDA)-approved indications for dapsone are leprosy, dermatitis herpetiformis, and acne vulgaris. However, it proved itself as an adjunctive therapeutic agent to many other skin disorders. In this review, we discuss existing evidence on the mechanisms of action of dapsone, its FDA-approved indications, off-label uses, and side effects.     

Pin tract infection of operatively treated supracondylar fractures in children: long-term functional outcomes and anatomical study

Purpose

The purpose of our study was to determine the long-term functional outcomes of pin tract infection after percutaneous pinning of displaced supracondylar humeral fractures in children, and to evaluate the potential for intracapsular pin placement based on pin configuration in cadaveric elbows.

Methods

We conducted a retrospective review of all patients requiring percutaneous pinning in a single institution over a 19-year period. The functional outcome assessment consisted of a telephone interview using the Disabilities of the Arm, Shoulder and Hand (DASH)] Outcome Measure and the Patient-Rated Elbow Evaluation (PREE) questionnaires. The risk of intracapsular pin placement was studied in cadaveric elbows for the three most common pin configurations: divergent lateral, parallel lateral, and medial and lateral crossed pins.

Results

Of 490 children, 21 (4.3 %) developed pin tract infection. There were 15 (3.1 %) superficial and six (1.2 %) deep infections (osteomyelitis and septic arthritis). Both DASH and PREE scores were excellent at a mean of 18 years post-surgery. The risk of intracapsular pin placement using parallel lateral pins was found to be greater (p < 0.05) than either crossed or divergent lateral pinning configurations.

Conclusions

Most infections after pinning of supracondylar humerus fractures are superficial and can be managed with pin removal, oral antibiotics, and local wound care. Septic arthritis and osteomyelitis are rare complications; when they do occur, they seem to be associated with parallel lateral pin configuration, though a causal relationship could not be established from the current study. Satisfactory long-term outcomes of these deep infections can be expected when treated aggressively with surgical debridement and intravenous antibiotics.     

Neurocognitive Outcome and White Matter Anisotropy in Childhood Acute Lymphoblastic Leukemia Survivors Treated with Different Protocols

Neurocognitive outcome affects the quality of life of ALL survivors. This study is aimed to assess the prevalence of neurocognitive dysfunction by psychometric and imaging tools in survivors of childhood ALL, treated with 3 different protocols and the effect of time elapsed since the end of chemotherapy. Sixty-two ALL survivors aged 6–18 years and treated in the period 1997–2007 and 60 healthy age and sex matched controls were subjected to neurocognitive testing using Wechsler Intelligence Scale for Children, Benton visual retention (BVRT) and Trail Making test (TMT), followed by diffusion weighed and diffusion tensor MRI for calculation of fraction anisotropy (FA). Survivors underwent revision of protocol and type of CNS therapy. Three different protocols were used: modified BFM 83, BFM 90, and CCG. Survivors treated with modified CCG protocol showed a significant decrease in all cognitive tests compared to control (p<.05); BFM 90 group had a significant lower IQ and longer TMT compared to both control and BFM 83 group and no significant difference was found in results of cognitive tests between BFM 83 and control group. Frontal FA was lower in CCG treated group compared to control, BFM 90 and BFM 83 groups (p<.05); meanwhile it was significantly lower in BFM 90 and BFM 83 groups compared to control group. We concluded that patients treated with modified CCG protocol showed the worst neurocognitive outcome among three assessed protocols. Frontal lobe FA might be an early marker for predicting the neurotoxicity in childhood ALL survivors.     

CHILD syndrome: A modified pathogenesis‐targeted therapeutic approach

Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects (CHILD syndrome) is a rare X‐linked dominant genodermatosis caused by mutations in the NAD(P) dependent steroid dehydrogenase‐like protein gene. Its defect leads to accumulation of toxic metabolic intermediates upstream from the pathway block and to the deficiency of bulk cholesterol, probably leading to altered keratinocyte membrane function, resulting in the phenotype seen in CHILD syndrome. Symptomatic treatment using emollients and retinoids to reduce scaling has long been used until recently, whereby new therapeutic means based on the pathogenesis‐targeted therapy have been developed. We subsequently chose to use the same pathogenesis‐based therapy using a 2% cholesterol and 2% lovastatin cream with or without glycolic acid in two of our patients. Improvement in CHILD skin lesions was seen as early as 4 weeks after initiation. The addition of glycolic acid helped improve the penetrance of the cholesterol and lovastatin cream into the thick waxy scales. Our study confirms the efficacy of the pathogenesis‐targeted therapy and introduces the possibility of modifying its formula by adding glycolic acid in order to improve the treatment.