News and Views

Published in IJCP March 2024 Around The Globe News and Views March 22, 2024 \| ijcp The Case for Fludrocortisone + Hydrocortisone in Septic Shock Administration of a combination of fludrocortisone and hydrocortisone reduced mortality by 12% among patients with septic shock compared to hydrocortisone alone, according to a study published in the American Journal of Respiratory and Critical Care Medicine.¹ The objective of this study was to compare the effectiveness and safety of fludrocortisone + hydrocortisone versus hydrocortisone alone versus placebo/usual care in adult patients with septic shock. The researchers conducted a systematic review and Bayesian network meta-analysis of randomized trials published in peer-reviewed journals. All-cause mortality at the last follow-up was set as the primary outcome of the study. The reference treatment used for comparison was placebo/usual care. Based on the analysis of 17 trials involving 7,688 patients, the combination of fludrocortisone + hydrocortisone demonstrated the lowest all-cause mortality at last follow-up, with a relative risk (RR) of 0.85 and a high probability (98.3%) of being superior, supported by moderate-certainty evidence. Hydrocortisone alone had a slightly higher RR of 0.97 and a lower probability (73.1%) of superiority, based on low-certainty evidence. The authors note that the comparison between fludrocortisone + hydrocortisone and hydrocortisone alone relied primarily on indirect evidence, with only two trials providing direct evidence. However, the combination therapy still showed a 12% lower risk of all-cause mortality compared to hydrocortisone alone, with an RR of 0.88 and a 94.2% probability of superiority, supported by moderate-certainty evidence. In adult septic shock patients, the combination of fludrocortisone + hydrocortisone was found to be associated with a lower risk of all-cause mortality at last follow-up compared to both placebo and hydrocortisone alone. However, it is important to note that owing to the paucity of head-to-head trials comparing fludrocortisone + hydrocortisone versus hydrocortisone alone; this network meta-analysis relied mainly on indirect evidence for this comparison, as per the authors. Although several sensitivity analyses and assessments were undertaken to ensure the robustness of our findings, it is crucial to consider these results while also acknowledging the heterogeneity of the included trials. Fludrocortisone is a very potent mineralocorticoid, while hydrocortisone has mineralocorticoid and glucocorticoid activity. The comparative activity of hydrocortisone to fludrocortisone is approximately 1 to 125-150; this ratio is mainly derived from the effects of hydrocortisone and fludrocortisone on sodium retention in the kidneys. There is evidence to suggest that in patients with sepsis, the production of mineralocorticoids is impaired considerably more than the synthesis of glucocorticoids. This deficiency in mineralocorticoid synthesis has been found to be associated with a higher risk of sepsis-related mortality.² Earlier studies have elucidated on the potential role of mineralocorticoids in septic shock. There are different isoforms of the mineralocorticoid receptor. Some of these isoforms can bind to both glucocorticoids and mineralocorticoids, while others specifically bind to mineralocorticoids. The deactivation of glucocorticoids ensures that mineralocorticoids have a strong interaction with mineralocorticoid receptors. These receptors are also present in immune cells and when activated, they can enhance leukocyte adhesion, which can be beneficial in eradicating bacterial infections. Experimental sepsis studies have shown that mineralocorticoids, such as fludrocortisone, can reduce the levels of histamine, serotonin and bradykinin in the plasma, leading to a faster reversal of shock.² Addition of fludrocortisone enhances the mineralocorticoid activity. By affecting salt and water balance in the body, mineralocorticoids may have a role in septic shock by restoring the effective blood volume through increased mineralocorticoid activity. On the other hand, glucocorticoids preferentially affect sugar metabolism and show sex hormone activities.³ These findings provide support for the beneficial effects of addition of fludrocortisone to hydrocortisone in lowering the risk of short-term mortality in these patients. References Teja B, et al. Effectiveness of fludrocortisone plus hydrocortisone versus hydrocortisone alone in septic shock: a systematic review and network meta-analysis of randomized controlled trials. Am J Respir Crit Care Med. 2024 Jan 25. Lai PC, et al. Do we need to administer fludrocortisone in addition to hydrocortisone in adult patients with septic shock? An updated systematic review with Bayesian network meta-analysis of randomized controlled trials and an observational study with target trial emulation. Crit Care Med. 2023 Dec 29. Yamamoto R, et al. Hydrocortisone with fludrocortisone for septic shock: a systematic review and meta-analysis. Acute Med Surg. 2020;7(1):e563. Endometriosis and Pregnancy Outcomes Pregnant women with stage III or IV endometriosis are likely to have a higher incidence of placenta previa compared to pregnant women with stage 1 or II endometriosis, suggests a study published in the European Review for Medical and Pharmacological Sciences.¹ But other pregnancy complications did not differ much in the two disease severity groups. Through this retrospective study, Zhao-Zhen Liu, from the Dept. of Obstetrics and Gynecology at the College of Clinical Medicine for Obstetrics, Gynecology and Pediatrics at Fujian Medical University, China, and coauthors aimed to investigate the impact of endometriosis on pregnancy and assess any potential pregnancy complications and neonatal outcomes in patients with pregnancies complicated by endometriosis. Their goal was to contribute to a better understanding of the impact of endometriosis on pregnancy outcomes. A total of 3,809 pregnant women who underwent cesarean section delivery at Fujian Maternity and Child Health Hospital in China between January 2014 and December 2020. Among them, 1,026 were diagnosed with endometriosis after the cesarean section, forming the endometriosis group. The control group consisted of 2,783 women without endometriosis. The endometriosis group was further categorized into subgroups based on the disease severity; the first subgroup consisted of 882 subjects with stage I or II endometriosis, while the second subgroup comprised 144 parturients with stage III or IV endometriosis. During the study, general data of all patients and medical records of pregnancy complications and neonatal outcomes were collected and retrospectively analyzed. Age, gestational age, gestation and parity times were comparable between endometriosis and control groups. Results showed no statistically significant differences in age, gestational age, gestation and parity times between all groups (p > 0.05). However, the incidence of pre-eclampsia and placenta previa in the endometriosis group was higher compared to the control group (p < 0.05). No significant between-group differences were observed with regard to other pregnancy complications such as chronic hypertension with pregnancy, pre-eclampsia with chronic hypertension, hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, gestational diabetes mellitus, pregestational diabetes mellitus, intrahepatic cholestasis of pregnancy, premature rupture of membranes and placental abruption. When the two subgroups were analyzed, patients with more severe endometriosis, stage III/IV were found to have higher incidence of placenta previa compared to those with stage I/II endometriosis (p < 0.05). Additionally, the amount of postpartum hemorrhage (1,000-1,500 mL) was significantly greater in the endometriosis group compared to the control group. However, there was no significant difference in the incidence of postpartum hemorrhage among patients with pregnancies complicated by endometriosis at different stages. These findings provide valuable insights into the potential risks and complications associated with endometriosis during pregnancy and suggest that endometriosis may contribute to an increased risk of certain pregnancy complications. They show that in pregnant women, endometriosis is associated with an increased incidence of placenta previa, and this correlation is influenced by the severity of the disease. Additionally, pregnant women with endometriosis have higher rates of pre-eclampsia and postpartum hemorrhage compared to women without endometriosis. It is important to consider these factors when managing and providing care for pregnant women with endometriosis. Reference Liu ZZ, et al. Effects of endometriosis on pregnancy outcomes in Fujian province. Eur Rev Med Pharmacol Sci. 2023;27(22):10968-78. Prognostic Factors in Acute Exacerbation of Idiopathic Pulmonary Fibrosis Long-term use of supplemental oxygen, the need for invasive mechanical ventilation upon admission, pre-exacerbation steroid use and increased neutrophils in bronchoalveolar lavage (BAL) are indicators of higher mortality risk in patients acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). These findings from a systematic review and meta-analysis were published in Respiratory Medicine.¹ To understand the factors that contribute to mortality in patients with AE-IPF, researchers from Canada, USA, UK, Norway and Australia conducted a systematic review and pairwise meta-analysis of factors associated with mortality in these patients. For this they searched databases such as Embase, Medline and CINAHL for studies that reported on the association between any prognostic factor and AE-IPF in adult patients. A total of 35 studies, involving over 18,000 patients, published between 1990 and 2022 were included in the analysis. Over two-thirds of them were from Japan with other participants from South Korea, Canada, China and the US. Their mean age ranged from 64.6 to 78.5 years and majorities were male. Review of these studies revealed several factors related to the risk of death in patients with AE-IPF. Long-term use of supplemental oxygen at baseline more than doubled the risk of death in patients with AE-IPF with adjusted hazard ratio (aHR) 2.52 with moderate certainty of evidence. Additionally, a diagnosis of IPF compared to non-IPF interstitial lung disease (ILD) was associated with an increased risk of death (aHR 2.19) with moderate certainty of evidence. Mortality was also increased in patients aged ≥80 years versus younger patients (aHR 2.98). Radiographic factors associated with higher risk of death in these patients were also identified. These included: a diffuse pattern on high-resolution computed tomography (HRCT) (vs. non-diffuse pattern) with aHR of 2.61 (with moderate certainty) and a higher CT score (aHR 1.14) with low certainty. Use of steroids before hospitalization for exacerbation increased the odds of mortality with aHR of 2.19. Patients with neutrophilia (% increase) in BAL during the exacerbation were at an increased risk of death with aHR of 1.02 (moderate certainty). Risk of mortality was higher among patients who needed invasive mechanical ventilation upon admission (aHR 3.74).² This study has defined factors that adversely affect prognosis in patients with AE-IPF. Identification of these factors can therefore help clinicians to define clinical management and treatment decisions and potentially improve outcomes in these patients. Nevertheless, the authors have called for further studies “to validate additional prognostic factors to inform IPF management”. References Pitre T, et al. Prognostic factors associated with mortality in acute exacerbations of idiopathic pulmonary fibrosis: a systematic review and meta-analysis. Respir Med. 2023;222:107515. Goldberg R. https://www.pulmonologyadvisor.com/home/topics/restrictive-lung-disease/prognostic-factors-linked-to-mortality-in-ae-ipf/. Dated Feb. 1, 2024. Accessed Feb. 2, 2024. Common Household Cleaning Products and Asthma Control Frequent use of household disinfectants and cleaning products in a week is strongly associated with uncontrolled asthma, says a study published in The Journal of Allergy and Clinical Immunology: In Practice. The risk increased with almost every day use.^1,2 This study examined the impact of household disinfectants and cleaning products (HDCPs), including irritants and green products, sprays and disinfecting wipes and asthma control using 2018 data from the French Web-based NutriNet-Santé cohort. A standardized questionnaire was used to assess asthma control and the use of HDCPs at home. Factors such as sex, age, smoking status, body mass index (BMI) and educational level were considered. In the overall study population of 37,043 patients, the mean age was 47.5 years; three-fourth of them were women. In addition, 12.5% were current smokers, 32.2% were classified as overweight (BMI 25 kg/m²), and ~64% participants had completed at least 2 years of university education. Sixty-two percent reported using at least 1 HDCP every week. Participants with current asthma and uncontrolled asthma tended to be younger, female, current smokers and overweight. Those with current asthma had higher education levels and those with uncontrolled asthma had lower educational status. Based on the analysis conducted on 37,043 adults, it was found that greater weekly use of HDCPs was strongly associated with uncontrolled asthma. Those who used irritants and green products almost daily (4-7 days/week) were at least twice more likely to have uncontrolled asthma with odds ratios (ORs) of 2.81 and 2.40, respectively (vs. those who used them for 1-3 days/week with ORs of 1.65 and 1.49, respectively). A similar association was noted with use of sprays (OR 2.69) (vs. 1.49 for 1-3 days/week use). Those who used disinfecting wipes were 3.5 times more likely to have poorly controlled asthma (OR 3.51) (vs. 2.2 for 1-3 days/week use). Notably, even when not used together with irritants and sprays, both disinfecting wipes (OR 1.99) and green products (OR 1.59) still showed statistically significant associations with uncontrolled asthma. Subjects with overweight showed stronger association between use of irritants, sprays and green products and current asthma. Likewise, the association was also strong among participants who did not have any household help compared to those who had household help. The use of irritants or sprays as household cleaning products are known to be associated with respiratory symptoms. Hence, green products and wipes are often used as alternatives to mitigate or minimize the potential respiratory risks while maintaining a clean and healthy household environment. By demonstrating an association between the weekly use of HDCPs, including green products or wipes and uncontrolled asthma, this study suggests that the use of HDCPs may have an impact on asthma symptoms and management. This study draws attention to triggers other than the conventionally known ones such as upper respiratory infections, environmental allergens (like pollen, dust mite), cigarette smoke and air pollution. It is important for health practitioners to be aware of the impact of common household cleaning items on asthma and consider it when developing treatment plans for their patients to improve and maintain asthma control. While they may not entirely be preventable, they can be controlled for a good quality of life. References Pacheco Da Silva E, et al. Household use of green cleaning products, disinfecting wipes, and asthma control among adults. J Allergy Clin Immunol Pract. 2023 Dec 25:S2213-2198(23)01392-2. https://www.healio.com/news/allergy-asthma/20240125/household-disinfectants-cleaning-products-associated-with-uncontrolled-asthma. Dated Jan. 25, 2024. Accessed Feb. 3, 2024. Predicting Occurrence of Hypothyroidism in OSA Patients with Lymphocyte Count A new study published in the journal BMC Pulmonary Medicine has suggested that the prevalence of hypothyroidism rises with increasing lymphocyte count in patients with obstructive sleep apnea (OSA).¹ Xiaoyan Fang from the Dept. of Respiratory and Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin in China and colleagues conducted this retrospective study to evaluate the association between lymphocytes and hypothyroidism specifically in patients with OSA. The study participants underwent routine blood tests, including thyroid profile and nocturnal sleep monitoring. The researchers used logistic regression analysis to identify independent predictors of hypothyroidism in OSA patients. Additionally, they determined the cut-off level of lymphocyte count using a receiver operating characteristic (ROC) analysis to determine the occurrence of hypothyroidism in these patients. They selected 920 patients attending the Sleep Center at the Tianjin Medical University General Hospital. The prevalence of hypothyroidism was found to be 4.46% (n = 41), the prevalence in male patients was 3.4% and in female patients, it was 6.6%. Around 95.5% (n = 879) had normal thyroid function. The BMI of OSA patients with hypothyroidism was higher (34.78) than in controls (32.38). Epworth Sleepiness Scale (ESS) scores were significantly higher in OSA patients with hypothyroidism versus controls (10 vs. 6). The researchers found that in the entire OSA population and male OSA patients, the lymphocyte percentage and lymphocyte count were significantly higher in the hypothyroid group compared to the control group. On subgroup analysis, the lymphocyte counts were markedly raised among OSA patients younger than 60 years old and those with mild to moderate OSA, the hypothyroid group had significantly higher lymphocyte counts compared to those with normal thyroid function. The study identified lymphocyte count, ESS, and sex as independent predictors of hypothyroidism development in OSA patients. The ROC curve analysis indicated that the risk of hypothyroidism rose with increasing lymphocyte count in the overall patient population, with an optimal diagnostic cut-off point of 2.5 × 10⁹/L. This study demonstrates a correlation between the number of lymphocytes and the prevalence of hypothyroidism in patients with OSA, which includes subclinical hypothyroidism and not just overt. As the number of lymphocytes increased, the prevalence of hypothyroidism increased. A higher lymphocyte count therefore can be used as an independent predictor of the occurrence of hypothyroidism in this group of patients. The two conditions also share clinical features such as excessive sleepiness during the day, lethargy, obesity. Lymphocyte count is a simple and an easily available test and therefore can be undertaken to diagnose hypothyroidism in OSA patients followed by appropriate management resulting in better patient outcomes. Nevertheless, researchers advocate further research to corroborate their findings and to understand the mechanisms of this association. Reference Fang X, et al. The association of lymphocyte with hypothyroidism in obstructive sleep apnea. BMC Pulm Med. 2024;24(1):60. Risk of Bone Fractures among Living Kidney Donors Living kidney donors face a lower overall risk for bone fractures compared to matched general population controls 25 years after donation. However, they are at a significantly greater risk of vertebral fractures, according to study published online January 2, 2024 in JAMA Network Open.¹ Hilal Maradit Kremers, MD, of the Division of Epidemiology and Dept. of Quantitative Health Sciences at Mayo Clinic in Rochester, Minnesota et al conducted a survey study, between December 2021 and July 2023, to compare the risk of fractures among living kidney donors with strictly matched controls from the general population who were eligible to donate a kidney but did not do so. The survey questionnaire about their bone health and fracture history was sent to 5,065 living kidney donors from 3 transplant centers in Minnesota and 16,156 population-based nondonor controls without a history of comorbidities that would have prevented kidney donation. Out of these, 2,132 living kidney donors and 2,014 nondonor controls responded to the survey. The main outcome measures were the rates of overall and site-specific fractures, which were compared between the two groups, using standardized incidence ratios (SIRs). Statistical analyses were performed between May and August 2023. According to the survey, the group of living kidney donors, consisting of 2,132 individuals, had an average age of 67.1 years. Among them, 1,245 were women, accounting for 58.4% of the total. On the other hand, the control group, consisting of 2,014 individuals, had an average age of 68.6 years. Among the controls, 1,140 were women, making up 56.6% of the total. The average time between donation or index date and the survey date was 24.2 years for the donors and 27.6 years for the controls. The survey found that the overall rate of fractures was significantly lower among living kidney donors compared to the controls (443 observed vs. 499.8 expected fractures) with a SIR of 0.89. However, there were significantly more vertebral fractures observed among living kidney donors than in the controls (51 observed vs. 36 expected) with an SIR of 1.42. Among men, there were 21 observed vertebral fractures versus 12.5 expected (SIR 1.67). According to the survey study, which assessed the potential impact of living kidney donation on fracture risk, it was observed that living kidney donors had a lower rate of overall fractures but a higher occurrence of vertebral fractures compared to the control group. This finding was observed after an average follow-up period of 25 years. This risk, according to the authors, can be attributed to several factors, including reductions in kidney mass, reduced serum 1,25-dihydroxyvitamin D levels and secondary increases in the levels of serum parathyroid hormone. These factors can contribute to decreased bone density resulting in increased susceptibility to fractures in living kidney donors. It is therefore important for health care providers to monitor and address these potential risks in order to ensure the well-being of living kidney donors. The study suggests that treatment with dietary supplements like vitamin D3 may help reduce the number of vertebral fractures and associated morbidity. Reference Maradit Kremers H, et al. Fracture risk among living kidney donors 25 years after donation. JAMA Netw Open. 2024;7(1):e2353005. Women More Likely to have Painful Diabetic Peripheral Neuropathy Female patients with diabetes are at risk of developing painful diabetic peripheral neuropathy (DPN) suggesting that factors other than the traditional cardiometabolic factors may also be at play in the genesis of painful neuropathy. These findings from a European study were published in the January 2024 issue of the journal Diabetologia.¹ Data from the EURODIAB Prospective Complications Study was analyzed to examine the incidence and risk factors for painful DPN. The study involved 3,250 participants with type 1 diabetes who were followed up for an average of 7.3 years. The methodology to evaluate DPN included clinical assessment, quantitative sensory testing and autonomic function tests. Painful DPN, defined as experiencing painful neuropathic symptoms in the legs among participants with confirmed DPN, was assessed at both baseline and follow-up. At baseline, at least one-quarter (25.2%) of the participants with DPN had painful neuropathy. Over follow-up, 23.5% other patients developed incident DPN. Of these, ~15% had painful DPN. The painful and painless DPN groups did not differ much in terms of clinical and demographic variables such as age, BMI, glycated hemoglobin (HbA1c), blood pressure and lipid profile. It was observed that a higher proportion of female participants developed incident painful DPN compared to painless DPN; 73% versus 48%, respectively. This sex difference remained significant even after adjusting for the duration of diabetes and HbA1c levels with OR of 2.69 for women versus men. Additionally, fewer patients with painful DPN had macro- or microalbuminuria compared to those with painless DPN; 15% versus 34%, respectively. This association also remained significant after adjusting for HbA1c levels, diabetes duration and sex. This study, for the first time, provides valuable insights into the risk factors for painful DPN and suggests female sex as a risk factor for the same. It raises the possibility that painful DPN may not solely be determined by traditional cardiometabolic risk factors such as HbA1c, diabetes duration, low-density lipoprotein (LDL) cholesterol, triglycerides, hypertension, smoking, BMI. It may also be influenced by psychosocial, cultural and genetic factors. It highlights the potential importance of sex differences in the pathophysiology of neuropathic pain in diabetes. Future studies should therefore explore these factors to further understand the development of painful DPN. Reference Elliott J, et al. Female sex is a risk factor for painful diabetic peripheral neuropathy: the EURODIAB prospective diabetes complications study. Diabetologia. 2024;67(1):190-8. Predictors of COVID-19-associated Pulmonary Aspergillosis Presence of chronic liver disease, chronic obstructive pulmonary disease (COPD), mechanical ventilation, use of steroids or interleukin (IL)-6 inhibitors as treatment for coronavirus disease 2019 (COVID-19) are some of the factors that were predictive of COVID-19-associated pulmonary aspergillosis (CAPA) in patients with severe COVID-19, suggests a study published online in The Lancet Respiratory Medicine.¹ The aim of this study designed as a systematic review and meta-analysis was to identify factors associated with CAPA. For this they identified 27 studies that compared data of patients with COVID-19, with and without CAPA involving a total of 6,848 patients after a search of the Ovid MEDLINE, Ovid Embase, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and the WHO COVID-19 Database from December 1, 2019, to July 27, 2023. Women comprised almost 40% of the study group. Over two-thirds required mechanical ventilation. The inclusion criteria involved case-control and cohort studies in adults (aged >18 years) that reported at least 6 cases of CAPA and assessed any risk factors for CAPA. Only studies that included a control population of COVID-19-positive individuals without aspergillosis were included in the analysis. Nearly 20% (n = 1,324) of the participants were diagnosed with CAPA with diagnosis rate varying from 2.5% (14 out of 566 patients) to 47.2% (58 out of 123 patients) across the studies. The onset of CAPA occurred within 3 to 18 days after admission in ICU. The analysis identified several risk factors associated with CAPA. These included pre-existing comorbidities such as chronic liver disease (OR 2.70), hematological malignancies (OR 2.47), COPD (OR 2.00) and cerebrovascular disease (OR 1.31). Additional risk factors included the use of invasive mechanical ventilation (OR 2.83), the use of renal replacement therapy (OR 2.26), treatment of COVID-19 with IL-6 inhibitors (OR 2.88) and treatment of COVID-19 with corticosteroids (OR 1.88). Patients with CAPA tended to be older than those without CAPA, with a mean age of 66.6 years compared to 63.5 years with mean difference of 2.90. The duration of mechanical ventilation was also longer in patients with CAPA (19.3 days) compared to those without CAPA (13.5 days) with mean difference 5.53 days. Also, in post-hoc analysis, patients with CAPA had a higher all-cause mortality rate compared to those without CAPA (OR 2.65). Patients with severe COVID-19 should be screened for CAPA. Awareness of the risk factors can help to detect at-risk patients. By implementing specific antifungal prophylactic measures, health care providers can aim to mitigate the risk of developing CAPA in this group of patients by potentially addressing the risk factors identified in this study. Adopting this approach may help in preventing or reducing the incidence of CAPA and its associated complications. Reference Gioia F, et al. Risk factors for COVID-19-associated pulmonary aspergillosis: a systematic review and meta-analysis. Lancet Respir Med. 2024;12(3):207-216.

Published in IJCP March 2024

Around The Globe

News and Views

March 22, 2024 | ijcp

The Case for Fludrocortisone + Hydrocortisone in Septic Shock

Administration of a combination of fludrocortisone and hydrocortisone reduced mortality by 12% among patients with septic shock compared to hydrocortisone alone, according to a study published in the American Journal of Respiratory and Critical Care Medicine.¹

The objective of this study was to compare the effectiveness and safety of fludrocortisone + hydrocortisone versus hydrocortisone alone versus placebo/usual care in adult patients with septic shock. The researchers conducted a systematic review and Bayesian network meta-analysis of randomized trials published in peer-reviewed journals. All-cause mortality at the last follow-up was set as the primary outcome of the study. The reference treatment used for comparison was placebo/usual care.

Based on the analysis of 17 trials involving 7,688 patients, the combination of fludrocortisone + hydrocortisone demonstrated the lowest all-cause mortality at last follow-up, with a relative risk (RR) of 0.85 and a high probability (98.3%) of being superior, supported by moderate-certainty evidence. Hydrocortisone alone had a slightly higher RR of 0.97 and a lower probability (73.1%) of superiority, based on low-certainty evidence.

The authors note that the comparison between fludrocortisone + hydrocortisone and hydrocortisone alone relied primarily on indirect evidence, with only two trials providing direct evidence. However, the combination therapy still showed a 12% lower risk of all-cause mortality compared to hydrocortisone alone, with an RR of 0.88 and a 94.2% probability of superiority, supported by moderate-certainty evidence.

In adult septic shock patients, the combination of fludrocortisone + hydrocortisone was found to be associated with a lower risk of all-cause mortality at last follow-up compared to both placebo and hydrocortisone alone. However, it is important to note that owing to the paucity of head-to-head trials comparing fludrocortisone + hydrocortisone versus hydrocortisone alone; this network meta-analysis relied mainly on indirect evidence for this comparison, as per the authors. Although several sensitivity analyses and assessments were undertaken to ensure the robustness of our findings, it is crucial to consider these results while also acknowledging the heterogeneity of the included trials.

Fludrocortisone is a very potent mineralocorticoid, while hydrocortisone has mineralocorticoid and glucocorticoid activity. The comparative activity of hydrocortisone to fludrocortisone is approximately 1 to 125-150; this ratio is mainly derived from the effects of hydrocortisone and fludrocortisone on sodium retention in the kidneys.

There is evidence to suggest that in patients with sepsis, the production of mineralocorticoids is impaired considerably more than the synthesis of glucocorticoids. This deficiency in mineralocorticoid synthesis has been found to be associated with a higher risk of sepsis-related mortality.²

Earlier studies have elucidated on the potential role of mineralocorticoids in septic shock.

There are different isoforms of the mineralocorticoid receptor. Some of these isoforms can bind to both glucocorticoids and mineralocorticoids, while others specifically bind to mineralocorticoids. The deactivation of glucocorticoids ensures that mineralocorticoids have a strong interaction with mineralocorticoid receptors. These receptors are also present in immune cells and when activated, they can enhance leukocyte adhesion, which can be beneficial in eradicating bacterial infections. Experimental sepsis studies have shown that mineralocorticoids, such as fludrocortisone, can reduce the levels of histamine, serotonin and bradykinin in the plasma, leading to a faster reversal of shock.²

Addition of fludrocortisone enhances the mineralocorticoid activity. By affecting salt and water balance in the body, mineralocorticoids may have a role in septic shock by restoring the effective blood volume through increased mineralocorticoid activity. On the other hand, glucocorticoids preferentially affect sugar metabolism and show sex hormone activities.³

These findings provide support for the beneficial effects of addition of fludrocortisone to hydrocortisone in lowering the risk of short-term mortality in these patients.

References

Teja B, et al. Effectiveness of fludrocortisone plus hydrocortisone versus hydrocortisone alone in septic shock: a systematic review and network meta-analysis of randomized controlled trials. Am J Respir Crit Care Med. 2024 Jan 25.

Lai PC, et al. Do we need to administer fludrocortisone in addition to hydrocortisone in adult patients with septic shock? An updated systematic review with Bayesian network meta-analysis of randomized controlled trials and an observational study with target trial emulation. Crit Care Med. 2023 Dec 29.

Yamamoto R, et al. Hydrocortisone with fludrocortisone for septic shock: a systematic review and meta-analysis. Acute Med Surg. 2020;7(1):e563.

Endometriosis and Pregnancy Outcomes

Pregnant women with stage III or IV endometriosis are likely to have a higher incidence of placenta previa compared to pregnant women with stage 1 or II endometriosis, suggests a study published in the European Review for Medical and Pharmacological Sciences.¹ But other pregnancy complications did not differ much in the two disease severity groups.

Through this retrospective study, Zhao-Zhen Liu, from the Dept. of Obstetrics and Gynecology at the College of Clinical Medicine for Obstetrics, Gynecology and Pediatrics at Fujian Medical University, China, and coauthors aimed to investigate the impact of endometriosis on pregnancy and assess any potential pregnancy complications and neonatal outcomes in patients with pregnancies complicated by endometriosis. Their goal was to contribute to a better understanding of the impact of endometriosis on pregnancy outcomes.

A total of 3,809 pregnant women who underwent cesarean section delivery at Fujian Maternity and Child Health Hospital in China between January 2014 and December 2020. Among them, 1,026 were diagnosed with endometriosis after the cesarean section, forming the endometriosis group. The control group consisted of 2,783 women without endometriosis.

The endometriosis group was further categorized into subgroups based on the disease severity; the first subgroup consisted of 882 subjects with stage I or II endometriosis, while the second subgroup comprised 144 parturients with stage III or IV endometriosis. During the study, general data of all patients and medical records of pregnancy complications and neonatal outcomes were collected and retrospectively analyzed. Age, gestational age, gestation and parity times were comparable between endometriosis and control groups.

Results showed no statistically significant differences in age, gestational age, gestation and parity times between all groups (p > 0.05). However, the incidence of pre-eclampsia and placenta previa in the endometriosis group was higher compared to the control group (p < 0.05).
No significant between-group differences were observed with regard to other pregnancy complications such as chronic hypertension with pregnancy, pre-eclampsia with chronic hypertension, hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, gestational diabetes mellitus, pregestational diabetes mellitus, intrahepatic cholestasis of pregnancy, premature rupture of membranes and placental abruption.

When the two subgroups were analyzed, patients with more severe endometriosis, stage III/IV were found to have higher incidence of placenta previa compared to those with stage I/II endometriosis (p < 0.05). Additionally, the amount of postpartum hemorrhage (1,000-1,500 mL) was significantly greater in the endometriosis group compared to the control group. However, there was no significant difference in the incidence of postpartum hemorrhage among patients with pregnancies complicated by endometriosis at different stages.

These findings provide valuable insights into the potential risks and complications associated with endometriosis during pregnancy and suggest that endometriosis may contribute to an increased risk of certain pregnancy complications. They show that in pregnant women, endometriosis is associated with an increased incidence of placenta previa, and this correlation is influenced by the severity of the disease. Additionally, pregnant women with endometriosis have higher rates of pre-eclampsia and postpartum hemorrhage compared to women without endometriosis. It is important to consider these factors when managing and providing care for pregnant women with endometriosis.

Reference

Liu ZZ, et al. Effects of endometriosis on pregnancy outcomes in Fujian province. Eur Rev Med Pharmacol Sci. 2023;27(22):10968-78.

Prognostic Factors in Acute Exacerbation of Idiopathic Pulmonary Fibrosis

Long-term use of supplemental oxygen, the need for invasive mechanical ventilation upon admission, pre-exacerbation steroid use and increased neutrophils in bronchoalveolar lavage (BAL) are indicators of higher mortality risk in patients acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). These findings from a systematic review and meta-analysis were published in Respiratory Medicine.¹

To understand the factors that contribute to mortality in patients with AE-IPF, researchers from Canada, USA, UK, Norway and Australia conducted a systematic review and pairwise meta-analysis of factors associated with mortality in these patients. For this they searched databases such as Embase, Medline and CINAHL for studies that reported on the association between any prognostic factor and AE-IPF in adult patients. A total of 35 studies, involving over 18,000 patients, published between 1990 and 2022 were included in the analysis. Over two-thirds of them were from Japan with other participants from South Korea, Canada, China and the US. Their mean age ranged from 64.6 to 78.5 years and majorities were male.

Review of these studies revealed several factors related to the risk of death in patients with AE-IPF.

Long-term use of supplemental oxygen at baseline more than doubled the risk of death in patients with AE-IPF with adjusted hazard ratio (aHR) 2.52 with moderate certainty of evidence. Additionally, a diagnosis of IPF compared to non-IPF interstitial lung disease (ILD) was associated with an increased risk of death (aHR 2.19) with moderate certainty of evidence. Mortality was also increased in patients aged ≥80 years versus younger patients (aHR 2.98).

Radiographic factors associated with higher risk of death in these patients were also identified. These included: a diffuse pattern on high-resolution computed tomography (HRCT) (vs. non-diffuse pattern) with aHR of 2.61 (with moderate certainty) and a higher CT score (aHR 1.14) with low certainty.

Use of steroids before hospitalization for exacerbation increased the odds of mortality with aHR of 2.19. Patients with neutrophilia (% increase) in BAL during the exacerbation were at an increased risk of death with aHR of 1.02 (moderate certainty). Risk of mortality was higher among patients who needed invasive mechanical ventilation upon admission (aHR 3.74).²

This study has defined factors that adversely affect prognosis in patients with AE-IPF. Identification of these factors can therefore help clinicians to define clinical management and treatment decisions and potentially improve outcomes in these patients. Nevertheless, the authors have called for further studies “to validate additional prognostic factors to inform IPF management”.

References

Pitre T, et al. Prognostic factors associated with mortality in acute exacerbations of idiopathic pulmonary fibrosis: a systematic review and meta-analysis. Respir Med. 2023;222:107515.

Goldberg R. https://www.pulmonologyadvisor.com/home/topics/restrictive-lung-disease/prognostic-factors-linked-to-mortality-in-ae-ipf/. Dated Feb. 1, 2024. Accessed Feb. 2, 2024.

Common Household Cleaning Products and Asthma Control

Frequent use of household disinfectants and cleaning products in a week is strongly associated with uncontrolled asthma, says a study published in The Journal of Allergy and Clinical Immunology: In Practice. The risk increased with almost every day use.^1,2

This study examined the impact of household disinfectants and cleaning products (HDCPs), including irritants and green products, sprays and disinfecting wipes and asthma control using 2018 data from the French Web-based NutriNet-Santé cohort. A standardized questionnaire was used to assess asthma control and the use of HDCPs at home. Factors such as sex, age, smoking status, body mass index (BMI) and educational level were considered. In the overall study population of 37,043 patients, the mean age was 47.5 years; three-fourth of them were women. In addition, 12.5% were current smokers, 32.2% were classified as overweight (BMI 25 kg/m²), and ~64% participants had completed at least 2 years of university education. Sixty-two percent reported using at least 1 HDCP every week.

Participants with current asthma and uncontrolled asthma tended to be younger, female, current smokers and overweight. Those with current asthma had higher education levels and those with uncontrolled asthma had lower educational status.

Based on the analysis conducted on 37,043 adults, it was found that greater weekly use of HDCPs was strongly associated with uncontrolled asthma.

Those who used irritants and green products almost daily (4-7 days/week) were at least twice more likely to have uncontrolled asthma with odds ratios (ORs) of 2.81 and 2.40, respectively (vs. those who used them for 1-3 days/week with ORs of 1.65 and 1.49, respectively). A similar association was noted with use of sprays (OR 2.69) (vs. 1.49 for 1-3 days/week use). Those who used disinfecting wipes were 3.5 times more likely to have poorly controlled asthma (OR 3.51) (vs. 2.2 for 1-3 days/week use). Notably, even when not used together with irritants and sprays, both disinfecting wipes (OR 1.99) and green products (OR 1.59) still showed statistically significant associations with uncontrolled asthma.

Subjects with overweight showed stronger association between use of irritants, sprays and green products and current asthma. Likewise, the association was also strong among participants who did not have any household help compared to those who had household help.

The use of irritants or sprays as household cleaning products are known to be associated with respiratory symptoms. Hence, green products and wipes are often used as alternatives to mitigate or minimize the potential respiratory risks while maintaining a clean and healthy household environment. By demonstrating an association between the weekly use of HDCPs, including green products or wipes and uncontrolled asthma, this study suggests that the use of HDCPs may have an impact on asthma symptoms and management.

This study draws attention to triggers other than the conventionally known ones such as upper respiratory infections, environmental allergens (like pollen, dust mite), cigarette smoke and air pollution. It is important for health practitioners to be aware of the impact of common household cleaning items on asthma and consider it when developing treatment plans for their patients to improve and maintain asthma control. While they may not entirely be preventable, they can be controlled for a good quality of life.

References

Pacheco Da Silva E, et al. Household use of green cleaning products, disinfecting wipes, and asthma control among adults. J Allergy Clin Immunol Pract. 2023 Dec 25:S2213-2198(23)01392-2.

https://www.healio.com/news/allergy-asthma/20240125/household-disinfectants-cleaning-products-associated-with-uncontrolled-asthma. Dated Jan. 25, 2024. Accessed Feb. 3, 2024.

Predicting Occurrence of Hypothyroidism in OSA Patients with Lymphocyte Count

A new study published in the journal BMC Pulmonary Medicine has suggested that the prevalence of hypothyroidism rises with increasing lymphocyte count in patients with obstructive sleep apnea (OSA).¹

Xiaoyan Fang from the Dept. of Respiratory and Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin in China and colleagues conducted this retrospective study to evaluate the association between lymphocytes and hypothyroidism specifically in patients with OSA. The study participants underwent routine blood tests, including thyroid profile and nocturnal sleep monitoring. The researchers used logistic regression analysis to identify independent predictors of hypothyroidism in OSA patients. Additionally, they determined the cut-off level of lymphocyte count using a receiver operating characteristic (ROC) analysis to determine the occurrence of hypothyroidism in these patients.

They selected 920 patients attending the Sleep Center at the Tianjin Medical University General Hospital. The prevalence of hypothyroidism was found to be 4.46% (n = 41), the prevalence in male patients was 3.4% and in female patients, it was 6.6%. Around 95.5% (n = 879) had normal thyroid function. The BMI of OSA patients with hypothyroidism was higher (34.78) than in controls (32.38). Epworth Sleepiness Scale (ESS) scores were significantly higher in OSA patients with hypothyroidism versus controls (10 vs. 6).

The researchers found that in the entire OSA population and male OSA patients, the lymphocyte percentage and lymphocyte count were significantly higher in the hypothyroid group compared to the control group. On subgroup analysis, the lymphocyte counts were markedly raised among OSA patients younger than 60 years old and those with mild to moderate OSA, the hypothyroid group had significantly higher lymphocyte counts compared to those with normal thyroid function.

The study identified lymphocyte count, ESS, and sex as independent predictors of hypothyroidism development in OSA patients. The ROC curve analysis indicated that the risk of hypothyroidism rose with increasing lymphocyte count in the overall patient population, with an optimal diagnostic cut-off point of 2.5 × 10⁹/L.

This study demonstrates a correlation between the number of lymphocytes and the prevalence of hypothyroidism in patients with OSA, which includes subclinical hypothyroidism and not just overt. As the number of lymphocytes increased, the prevalence of hypothyroidism increased. A higher lymphocyte count therefore can be used as an independent predictor of the occurrence of hypothyroidism in this group of patients. The two conditions also share clinical features such as excessive sleepiness during the day, lethargy, obesity. Lymphocyte count is a simple and an easily available test and therefore can be undertaken to diagnose hypothyroidism in OSA patients followed by appropriate management resulting in better patient outcomes. Nevertheless, researchers advocate further research to corroborate their findings and to understand the mechanisms of this association.

Reference

Fang X, et al. The association of lymphocyte with hypothyroidism in obstructive sleep apnea. BMC Pulm Med. 2024;24(1):60.

Risk of Bone Fractures among Living Kidney Donors

Living kidney donors face a lower overall risk for bone fractures compared to matched general population controls 25 years after donation. However, they are at a significantly greater risk of vertebral fractures, according to study published online January 2, 2024 in JAMA Network Open.¹

Hilal Maradit Kremers, MD, of the Division of Epidemiology and Dept. of Quantitative Health Sciences at Mayo Clinic in Rochester, Minnesota et al conducted a survey study, between December 2021 and July 2023, to compare the risk of fractures among living kidney donors with strictly matched controls from the general population who were eligible to donate a kidney but did not do so. The survey questionnaire about their bone health and fracture history was sent to 5,065 living kidney donors from 3 transplant centers in Minnesota and 16,156 population-based nondonor controls without a history of comorbidities that would have prevented kidney donation. Out of these, 2,132 living kidney donors and 2,014 nondonor controls responded to the survey. The main outcome measures were the rates of overall and site-specific fractures, which were compared between the two groups, using standardized incidence ratios (SIRs). Statistical analyses were performed between May and August 2023.

According to the survey, the group of living kidney donors, consisting of 2,132 individuals, had an average age of 67.1 years. Among them, 1,245 were women, accounting for 58.4% of the total. On the other hand, the control group, consisting of 2,014 individuals, had an average age of 68.6 years. Among the controls, 1,140 were women, making up 56.6% of the total.

The average time between donation or index date and the survey date was 24.2 years for the donors and 27.6 years for the controls.

The survey found that the overall rate of fractures was significantly lower among living kidney donors compared to the controls (443 observed vs. 499.8 expected fractures) with a SIR of 0.89. However, there were significantly more vertebral fractures observed among living kidney donors than in the controls (51 observed vs. 36 expected) with an SIR of 1.42. Among men, there were 21 observed vertebral fractures versus 12.5 expected (SIR 1.67).

According to the survey study, which assessed the potential impact of living kidney donation on fracture risk, it was observed that living kidney donors had a lower rate of overall fractures but a higher occurrence of vertebral fractures compared to the control group. This finding was observed after an average follow-up period of 25 years. This risk, according to the authors, can be attributed to several factors, including reductions in kidney mass, reduced serum 1,25-dihydroxyvitamin D levels and secondary increases in the levels of serum parathyroid hormone. These factors can contribute to decreased bone density resulting in increased susceptibility to fractures in living kidney donors.

It is therefore important for health care providers to monitor and address these potential risks in order to ensure the well-being of living kidney donors. The study suggests that treatment with dietary supplements like vitamin D3 may help reduce the number of vertebral fractures and associated morbidity.

Reference

Maradit Kremers H, et al. Fracture risk among living kidney donors 25 years after donation. JAMA Netw Open. 2024;7(1):e2353005.

Women More Likely to have Painful Diabetic Peripheral Neuropathy

Female patients with diabetes are at risk of developing painful diabetic peripheral neuropathy (DPN) suggesting that factors other than the traditional cardiometabolic factors may also be at play in the genesis of painful neuropathy. These findings from a European study were published in the January 2024 issue of the journal Diabetologia.¹

Data from the EURODIAB Prospective Complications Study was analyzed to examine the incidence and risk factors for painful DPN. The study involved 3,250 participants with type 1 diabetes who were followed up for an average of 7.3 years. The methodology to evaluate DPN included clinical assessment, quantitative sensory testing and autonomic function tests. Painful DPN, defined as experiencing painful neuropathic symptoms in the legs among participants with confirmed DPN, was assessed at both baseline and follow-up.

At baseline, at least one-quarter (25.2%) of the participants with DPN had painful neuropathy. Over follow-up, 23.5% other patients developed incident DPN. Of these, ~15% had painful DPN. The painful and painless DPN groups did not differ much in terms of clinical and demographic variables such as age, BMI, glycated hemoglobin (HbA1c), blood pressure and lipid profile.

It was observed that a higher proportion of female participants developed incident painful DPN compared to painless DPN; 73% versus 48%, respectively. This sex difference remained significant even after adjusting for the duration of diabetes and HbA1c levels with OR of 2.69 for women versus men. Additionally, fewer patients with painful DPN had macro- or microalbuminuria compared to those with painless DPN; 15% versus 34%, respectively. This association also remained significant after adjusting for HbA1c levels, diabetes duration and sex.

This study, for the first time, provides valuable insights into the risk factors for painful DPN and suggests female sex as a risk factor for the same. It raises the possibility that painful DPN may not solely be determined by traditional cardiometabolic risk factors such as HbA1c, diabetes duration, low-density lipoprotein (LDL) cholesterol, triglycerides, hypertension, smoking, BMI. It may also be influenced by psychosocial, cultural and genetic factors. It highlights the potential importance of sex differences in the pathophysiology of neuropathic pain in diabetes. Future studies should therefore explore these factors to further understand the development of painful DPN.

Reference

Elliott J, et al. Female sex is a risk factor for painful diabetic peripheral neuropathy: the EURODIAB prospective diabetes complications study. Diabetologia. 2024;67(1):190-8.

Predictors of COVID-19-associated Pulmonary Aspergillosis

Presence of chronic liver disease, chronic obstructive pulmonary disease (COPD), mechanical ventilation, use of steroids or interleukin (IL)-6 inhibitors as treatment for coronavirus disease 2019 (COVID-19) are some of the factors that were predictive of COVID-19-associated pulmonary aspergillosis (CAPA) in patients with severe COVID-19, suggests a study published online in The Lancet Respiratory Medicine.¹

The aim of this study designed as a systematic review and meta-analysis was to identify factors associated with CAPA. For this they identified 27 studies that compared data of patients with COVID-19, with and without CAPA involving a total of 6,848 patients after a search of the Ovid MEDLINE, Ovid Embase, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and the WHO COVID-19 Database from December 1, 2019, to July 27, 2023. Women comprised almost 40% of the study group. Over two-thirds required mechanical ventilation. The inclusion criteria involved case-control and cohort studies in adults (aged >18 years) that reported at least 6 cases of CAPA and assessed any risk factors for CAPA. Only studies that included a control population of COVID-19-positive individuals without aspergillosis were included in the analysis.

Nearly 20% (n = 1,324) of the participants were diagnosed with CAPA with diagnosis rate varying from 2.5% (14 out of 566 patients) to 47.2% (58 out of 123 patients) across the studies. The onset of CAPA occurred within 3 to 18 days after admission in ICU.

The analysis identified several risk factors associated with CAPA. These included pre-existing comorbidities such as chronic liver disease (OR 2.70), hematological malignancies (OR 2.47), COPD (OR 2.00) and cerebrovascular disease (OR 1.31). Additional risk factors included the use of invasive mechanical ventilation (OR 2.83), the use of renal replacement therapy (OR 2.26), treatment of COVID-19 with IL-6 inhibitors (OR 2.88) and treatment of COVID-19 with corticosteroids (OR 1.88).

Patients with CAPA tended to be older than those without CAPA, with a mean age of 66.6 years compared to 63.5 years with mean difference of 2.90.

The duration of mechanical ventilation was also longer in patients with CAPA (19.3 days) compared to those without CAPA (13.5 days) with mean difference 5.53 days. Also, in post-hoc analysis, patients with CAPA had a higher all-cause mortality rate compared to those without CAPA (OR 2.65).

Patients with severe COVID-19 should be screened for CAPA. Awareness of the risk factors can help to detect at-risk patients. By implementing specific antifungal prophylactic measures, health care providers can aim to mitigate the risk of developing CAPA in this group of patients by potentially addressing the risk factors identified in this study. Adopting this approach may help in preventing or reducing the incidence of CAPA and its associated complications.

Reference

Gioia F, et al. Risk factors for COVID-19-associated pulmonary aspergillosis: a systematic review and meta-analysis. Lancet Respir Med. 2024;12(3):207-216.

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