Fatigue, sleepiness and sleep quality are SARS-CoV-2 variant independent in patients with long COVID symptoms.

Acute infections with SARS-CoV-2 variants of concerns (VOCs) differ in clinical presentation. Discrepancies in their long-term sequelae, commonly referred to as long COVID, however, remain to be explored. We retrospectively analyzed data of 287 patients presented at the post-COVID care of the Pulmonology Department, Semmelweis University, Budapest, Hungary, and infected with SARS-CoV-2 during a period of 3 major epidemic waves in Hungary (February-July 2021, VOC: B.1.1.7, Alpha, N = 135; August-December 2021, VOC: B.1.617.2, Delta, N = 89; and January-June 2022, VOC: B.1.1.529, Omicron; N = 63), > 4 weeks after acute COVID-19. Overall, the ratio of long COVID symptomatic (LC) and asymptomatic (NS) patients was 2:1. Self-reported questionnaires on fatigue (Fatigue Severity Scale, FSS), sleepiness (Epworth Sleepiness Scale, ESS) and sleep quality (Pittsburgh Sleep Quality Index, PSQI) showed higher scores for LC (4.79 ± 0.12, 7.45 ± 0.33 and 7.46 ± 0.27, respectively) than NS patients (2.85 ± 0.16, 5.23 ± 0.32 and 4.26 ± 0.29, respectively; p < 0.05 for all vs. LC). By comparing data of the three waves, mean FSS and PSQI scores of LC patients, but not ESS scores, exceeded the normal range in all, with no significant inter-wave differences. Considering FSS ≥ 4 and PSQI > 5 cutoff values, LC patients commonly exhibited problematic fatigue (≥ 70%) and poor sleep quality (> 60%) in all three waves. Comparative analysis of PSQI component scores of LC patients identified no significant differences between the three waves. Our findings highlight the importance of concerted efforts to manage both fatigue and sleep disturbances in long COVID patient care. This multifaceted approach should be followed in all cases infected with either VOCs of SARS-CoV-2.

Remdesivir in Solid Organ Recipients for COVID-19 Pneumonia.

Solid organ transplant (SOT) recipients represent a vulnerable patient population and are of high risk for airborne viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). Treatment of COVID-19 is still challenging, as no proven therapeutic regimen is available for immunocompromised patients. Our aim was to evaluate the efficacy and safety of remdesivir (RDV) therapy in infected hospitalized SOT patients. All transplanted recipients (N = 25; lung: 19; kidney: 3, liver: 2, heart: 1) who needed hospital care were reviewed in the time period between September 2020 and May 2021 out of the 945 patients treated at the Department. Case control matched patients receiving RDV (all in need of supplementary oxygen) and standard of care (SOC) were included as controls. Among the 25 SOT patients (female:male = 11:14; average age = 53.2 ± 12.7 years), 15 received RDV medication (RDV-TX), and in 10 cases SOC treatment was used (SOC-TX). Significantly worse clinical score was noted in RDV patients compared with RDV-TX; however, transfer to a higher intensity care unit as well as 60-day survival of RDV-TX patients were significantly worse. All SOT fatalities within 60 days of follow-up were lung transplant recipients (6 out of 19 lung transplant patients). No adverse events were noted related to RDV therapy. In SOT patients, especially lung transplant recipients, with severe COVID-19 needing supplementary oxygen, RDV treatment was safe; however, outcome was significantly worse as compared with nontransplanted individuals with initially worse clinical parameters.

The characteristics of upper airway edema in hereditary and acquired angioedema with C1-inhibitor deficiency.

BACKGROUND: Angioedemas localized in the upper airway are potentially life threatening, and without proper treatment, they may lead to death by suffocation. Upper airway edemas (UAE) in bradykinin-mediated angioedemas can even be the first symptoms of the disease. METHODS: Our survey was performed with a retrospective long-term follow-up method from the medical history of 197 hereditary (C1-INH-HAE) and 20 acquired C1-inhibitor deficiency (C1-INH-AAE), 3 factor XII and 3 plasminogen gene mutation (FXII-HAE, PLG-HAE) patients treated at our center between 1990 and 2020. The UAE group included edemas localized to the mesopharynx, hypopharynx, and larynx, as narrowing of these anatomical regions can lead to suffocation. RESULTS: 98/197 C1-INH-HAE (47 families) and 13/20 C1-INH-AAE, 1/3 PLG-HAE, 1/3 FXII-HAE patients had experienced UAE at least once according to their medical history. In case of C1-INH-HAE patients, in 6/47 families who had undiagnosed ancestors had 13 members who died of suffocation. After the diagnosis, 1-1 member of two families died of UAE. 44/64 C1-INH-HAE patients did not smoke, 20/64 did. The occurrence of UAE was significantly higher in smoker patients. We analyzed 7607 HAE attacks of 56/98 patients. Out of all attacks, the incidence of UAE in the C1-INH-HAE group was 4%, and 9.5% in the C1-INH-AAE group, respectively. CONCLUSION: Early diagnosis is key in bradykinin-mediated angioedemas cases, since the patient must be provided with adequate treatment; and also it is essential to inform patients about the importance of avoiding the trigger factors and the early symptoms of UAE, as these measures could significantly decrease the incidence of lethal UAEs.

From genomes to diaries: a 3-year prospective, real-life study of ragweed-specific sublingual immunotherapy.

During the last decades, the prevalence of allergy has dramatically increased. Allergen-specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease, but there are still many questions and unmet needs hindering its widespread use to fulfill its treatment potential and maximize its benefits for the society. To provide a comprehensive phenome-wide overview in sublingual immunotherapy, using ragweed allergy as a target, we planned and carried out a longitudinal, prospective, observational, open-label study (DesensIT). In this paper we present challenges of using deep and comprehensive phenotypes embracing biological, clinical and patient-reported outcomes in allergen-specific immunotherapy and show how we designed the DesensIT project to optimize data collection, processing and evaluation.

Thyroid hormones and complement parameters in hereditary angioedema with C1-inhibitor deficiency.

BACKGROUND: Thyroid hormones control and up-regulate the synthesis of many plasma proteins. OBJECTIVE: To explore possible associations between thyroid hormone and complement levels in patients with hereditary angioedema resulting from the deficiency of the C1-inhibitor (C1-INH-HAE). METHODS: In this case-control study, serum thyrotropin, free triiodothyronine (FT3), and free thyroxine (FT4) levels, anti-thyroid peroxidase and antithyroglobulin antibody titers, and C1-INH concentrations were measured in 117 euthyroid patients with C1-INH-HAE and compared with their clinical properties. The control group comprised 150 healthy, age- and sex-matched, euthyroid individuals. RESULTS: The thyrotropin and antithyroglobulin levels were similar between the patients and the controls. Significantly lower FT3 (P < .001) and FT4 (P = .002) levels, as well as higher anti-thyroid peroxidase titers (P < .001), were seen in the patients with C1-INH-HAE. The proportion of patients with reduced C1-INH activity was greater among those with below-median FT4 levels than among those with above-median values (P = .02). Patients who experienced more edematous attacks per year had lower FT4 levels (within the normal range) than those afflicted by fewer episodes (P = .01). The FT3 and FT4 levels were significantly higher in patients undergoing long-term danazol therapy than in those who did not receive this drug (P = .01 and P = .02, respectively). The proportion of patients with FT4 levels in the below-median range was higher in the subset with increased d-dimer concentration (P = .009). CONCLUSION: Minor variations of the thyroid hormone levels (within the reference range) can influence the function of C1-INH in C1-INH-HAE. Our findings suggest a role for the endocrine system in the pathophysiology of C1-INH-HAE.

Relationship of Circulating C5a and Complement Factor H Levels With Disease Control in Pregnant Women With Asthma.

BACKGROUND: Asthma often complicates pregnancy and represents a risk of serious pregnancy complications. The complement system contributes to asthma pathogenesis and is up-regulated in healthy gestation as well. The anaphylatoxin C5a has a major pro-inflammatory role, and the complement factor H is a main soluble regulator protein both in asthma and during pregnancy; however, peripheral levels of these complement factors and their relationship to disease control have not yet been evaluated in pregnant subjects with asthma. METHODS: The present study aimed to investigate circulating C5a and complement factor H levels in asthma (non-pregnant subjects with asthma; n = 19) and in pregnancy with asthma (pregnant subjects with asthma; n = 22), compared with healthy non-pregnant (n = 21) and healthy pregnant women (n = 13) and to test their relationship to clinical parameters of asthma (lung function, airway inflammation, and symptoms). RESULTS: Circulating C5a levels were higher in the pregnant asthma subject group compared with the healthy non-pregnant, healthy pregnant, and non-pregnant asthma groups: median 2.629 (interquartile range [IQR] 2.257-3.052) ng/mL versus 1.84 (IQR 1.576-2.563), 1.783 (IQR 0.6064-2.786), and 2.024 (IQR 1.232-2.615) ng/mL, respectively (P = .02 in all cases). C5a correlated negatively with FEV1 (r = -0.44, P = .039) and FVC values (r = -0.64, P = .001) in the pregnant asthma group and positively with fraction of exhaled nitric oxide levels in the non-pregnant asthma group (n = 12, r = 0.78, P = .004). Complement factor H levels were elevated in both the healthy pregnant and pregnant asthma subject groups compared with the healthy non-pregnant group (median 1,082 [IQR 734.9-1,224] and 910.7 [IQR 614.5-1076] µg/mL vs. 559.7 [IQR 388.7-783.1] µg/mL, P = .002 and P = .004, respectively) but not in the pregnant asthma group compared with the non-pregnant asthma group (median 687.4 [IQR 441.6-947.6] µg/mL, P = .10). CONCLUSIONS: Asthma during pregnancy increases the circulating level of pro-inflammatory C5a, which is accompanied by impaired lung function and partly counteracted by the gestation-specific elevation of regulatory complement factor H level (detected in pregnancy both in healthy and subjects with asthma).

The influence of trigger factors on hereditary angioedema due to C1-inhibitor deficiency.

BACKGROUND: Hereditary angioedema (HAE) resulting from C1-inhibitor deficiency is characterized by attacks of subcutaneous and submucosal edema. Many factors have been presumed to induce edema. Our study analyzed these factors in a fairly large patient population. METHODS: In the first stage of our study, we analyzed the data recorded by 92 subjects in their patient diaries over seven years. The second phase included 27 HAE patients, who had been completing the diary entry 'Trigger factors' every day for seven months whether or not they had experienced an attack. RESULTS: During the initial stage, 91% of the subjects described some factor possibly related to the onset of an attack. They could identify a trigger factor - most commonly (21%) mental stress - in 30% of the 3176 attacks. We found a significant (p < 0.001) difference in the distribution of the trigger factors of the edematous attacks of different locations. The 27 participants of the second phase identified 882 potential trigger factors and recorded 365 attacks. Of these, 246 (67%) occurred on days when the patients identified a potential trigger factor. The likelihood of edema-formation associated with the latter was as follows: menstruation - 63%, infection - 38%, mental stress - 26%, physical exertion - 25%, meteorological changes - 21%, fatigue - 17%. CONCLUSION: This analysis of the trigger factors explored, for the first time, their potential role in inducing HAE attacks. Our findings might open new perspectives in extending the indications for edema-prophylaxis, and could contribute to a better understanding of the pathomechanism of HAE attacks.

Lack of increased prevalence of immunoregulatory disorders in hereditary angioedema due to C1-inhibitor deficiency.

Hereditary angioedema due to deficiency of C1-INH (HAE-C1-INH) is associated with enhanced consumption of the early complement components, which may predispose for autoimmune disease. We assessed the prevalence of such disorders among HAE- C1-INH patients and their impact on the natural course of HAE-C1-INH. Clinical data and immunoserological parameters of 130 HAE-C1-INH and 174 non-C1-INH-deficient patients with angioedema were analyzed. In our study, the incidence of immunoregulatory disorders was 11.5% in the population of HAE-C1-INH patients and 5.2% among non-C1-INH-deficient controls with angioedema. Immunoserology screening revealed a greater prevalence of anticardiolipin IgM (p=0.0118) among HAE-C1-INH patients, than in those with non-C1-INH-deficient angioedema. We did not find higher prevalence of immunoregulatory disorders among our HAE-C1-INH patients. However, in patients with confirmed immunoregulatory disorders, the latter influenced both the severity of HAE-C1-INH and the effectiveness of its long-term management. Appropriate management of the immunoregulatory disease thus identified improves the symptoms of HAE-C1-INH.

Association of celiac disease and hereditary angioedema due to C1-inhibitor deficiency. Screening patients with hereditary angioedema for celiac disease: is it worth the effort?

OBJECTIVE: Hereditary angioedema due to C1-inhibitor deficiency is a life-threatening condition, which manifests as edematous attacks involving subcutaneous tissues and/or the upper airway/gastrointestinal mucosa. Celiac disease is a gluten-sensitive small intestinal disorder that can lead to severe villous atrophy, malabsorption, and malignancy. Both hereditary angioedema and celiac disease may present with abdominal symptoms. Our aim was to study the occurrence of celiac disease in the hereditary angioedema population, as well as to analyze the clinical course of cases with both diseases. METHODS: One hundred and twenty-eight patients with hereditary angioedema were screened for celiac disease, using serological methods [antiendomysial antibodies-immunoglobulin A (IgA), antiendomysial antibodies-IgG and tissue transglutaminase-IgA, tissue transglutaminase-IgG]. Clinical data of a child with hereditary angioedema and celiac disease diagnosed earlier were added to the dataset to be analyzed. Thus, the total number of patients was 129, comprising 107 adults and 22 pediatric patients. In patients with celiac disease, molecular genetics analysis (human leukocyte antigen-DQA1, human leukocyte antigen-DQB1) was carried out along with the introduction of a gluten-free diet and regular follow-up. RESULTS: Four out of the 22 children were diagnosed with celiac disease in our hereditary angioedema population. The prevalence of celiac disease among our pediatric patients with hereditary angioedema (22 children) was higher than in the general population (18.1 vs. 1.2%). Switching from the wheat starch-containing tranexamic acid product to danazol and introducing a gluten-free diet mitigated abdominal symptoms of hereditary angioedema. CONCLUSION: Similarities between the symptoms of hereditary angioedema and celiac disease may cause difficulties in differential diagnosis, as well as in choosing the appropriate therapy. In our opinion, screening hereditary angioedema patients for celiac disease is warranted if abdominal attacks or neurological symptoms persist despite adequate management. Complement testing is recommended whenever abdominal symptoms persist despite the histological and serological remission of gluten-sensitive enteropathy after the introduction of a gluten-free diet.

The natural history of hereditary angioedema and the impact of treatment with human C1-inhibitor concentrate during pregnancy: a long-term survey.

OBJECTIVE: The course of hereditary angioedema (HAE) and the efficacy and safety of human C1-INH concentrate were appraised during pregnancy and the postpartum period, in patients with HAE. STUDY DESIGN: Retrospective analysis of clinical data on 118 pregnancies (82 full-term and 36 abortions) in 41 female patients, extracted from the National HAE Registry, medical charts and patient diaries. RESULTS: HAE attack frequency increases in 48% of pregnancies, whereas 33% of pregnancies were associated with mitigation of clinical signs and 19% of the pregnancies had no influence on the course of HAE, as compared to disease severity seen during the 2-year period preceding the pregnancy. During 46 full-term pregnancies, 26 patients reported attacks; 52% of these occurred in the third trimester. Abdominal attacks are the most common presentation of HAE during pregnancy. Attack number was significantly higher in patients who had sustained their initial attack before 8 years of age. Attack number increased during the third trimester if the fetus was afflicted by HAE. During the postpartum period, attacks occurred in 6/82 pregnancies. Patients received 91 vials of C1-INH concentrate altogether for the relief of acute attacks and for short- or long-term prophylaxis during pregnancy. This therapy was effective in all instances; no adverse effects were observed. CONCLUSIONS: Pregnancy can either aggravate or mitigate edematous attacks, or alternatively, it may have no influence on the severity of the disease. According to our experience, C1-INH concentrate is an effective and safe therapeutic option during pregnancy.

The effect of long-term danazol prophylaxis on liver function in hereditary angioedema-a longitudinal study.

BACKGROUND: Danazol is a drug most widely used for the prophylaxis of hereditary angioedema resulting from the deficiency of the C1-inhibitor. Potential hepatotoxic or liver tumor-inducing side effects of long-term danazol prophylaxis have been investigated during the follow-up of hereditary angioedema patients. METHODS: Characteristic parameters of liver function (including bilirubin, GOT, GPT, gammaGT, total protein, ALP, LDH), as well as findings of viral serology screens and abdominal ultrasonography-determined during years 0 and 5 of follow-up of patient groups taking/not taking danazol-have been reviewed and analyzed comparatively. RESULTS: From a population of 126 hereditary angioedema patients, 46 subjects taking danazol and another 46 not taking danazol fulfilled the inclusion criteria. Longitudinal follow-up did not reveal any clinically relevant difference between the liver function parameters determined in years 0 and 5 in the two groups. Abdominal ultrasound did not detect neoplastic or other potentially treatment-related alterations of the liver parenchyma. There were no discontinuations of treatment during the study. CONCLUSIONS: Our results clearly suggest that, administered at the lowest effective dose, danazol does not induce liver injury in hereditary angioedema patients.

Mathematical analysis of clinical data reveals a homunculus of bacterial mimotopes protecting from autoimmunity via oral tolerance in human.

Oral tolerance (OT) means systemic immunological unresponsiveness to harmless antigens present in the gastrointestinal tract. We presumed that tolerance to these antigens may also protect self-proteins that show immunological similarity to the intestinal normal flora. To investigate the existence and in vivo relevance of such a tolerogenic molecular mimicry, we focused our attention to Autoimmune Polyendocrine Syndrome type 1 (APS1) and Hemolysis, Elevated Liver Enzymes, Low Platelet count (HELLP) syndrome. APS1 is a human form of Autoimmune Regulator (AIRE) dysfunction with severely impaired central immunotolerance to a specific set of autoantigens, allowing investigation of tolerogenic mimicry by itself, without a disturbing background. HELLP syndrome is a mediocre manifestation of thrombotic microangiopathy, complicating pregnancy, with platelet-fibrin deposits in small blood vessels and transient development of autoantibodies. Impaired microcirculation in the liver is well described, while intestinal ischemia is possible but has not yet been studied. As the harmless nature of an antigen is essential for OT, ischemia-induced bacterial microinvasion represses this process. In case that oral tolerance to a bacterial homunculus is an existing way of self-protection and has an in vivo relevance when central tolerance is intact, significant intestinal ischemia--if present--is expected to promote autoimmunity in HELLP syndrome. We used an experimentally validated, highly reliable mathematical algorithm to predict the extent of immunological similarity between a certain autoantigen and intestinal bacteria. We found a strong negative correlation between the similarity of autoantigens to intestinal bacteria and the production of specific autoantibodies in APS1 (R=-0.70, P=0.002), while a positive correlation was observed in patients with predominantly the severe/moderately severe form of HELLP syndrome according to Mississippi classification (R=0.94, P=0.005). Autoantigen length inversely correlated with the production of autoantibodies in APS1 (R=-0.68, P=0.004). As a longer chain with more epitopes associates with an increased possibility of mimicry to any proteome, molecular mimicry in general--regarding at least major tissue-specific autoantigens--seems to be rather protective. Our calculations support the hypothesis that OT to an intestinal "bacterial homunculus" is an in vivo relevant mechanism of self-protection in humans, furthermore, HELLP syndrome presumably associates with significant intestinal ischemia and leak, resulting in transient autoimmunity via loss of OT.