Treatment of pulmonary mucormycosis with adjunctive nebulized amphotericin B (MUCONAB trial): Results of an open-label randomized controlled trial.

BACKGROUND: The role of nebulized amphotericin B (NAB) in managing pulmonary mucormycosis (PM) is unknown. METHODS: In this open-label trial, we randomized PM subjects to receive either intravenous liposomal amphotericin B (control arm, 3-5 mg/kg/day) alone or along with nebulized amphotericin B deoxycholate (NAB, 10 mg twice a day, every alternate day). The primary outcomes were: (1) overall response ('success' [complete or partial response] or 'failure' [stable disease, progressive disease, or death]) at 6 weeks; and (2) the proportion of subjects with adverse events (AE). The key secondary outcome was 90-day mortality. We performed a modified intention-to-treat (mITT) analysis where we included only subjects receiving at least a single dose of NAB. RESULTS: Fifteen and 17 subjects were randomized to the control and NAB arms; two died before the first dose of NAB. Finally, we included 30 subjects (15 in each arm; mean age 49.8 years; 80% men) for the mITT analysis. Diabetes mellitus (n = 27; 16/27 were COVID-19-associated PM) was the most common predisposing factor. The overall treatment success was not significantly different between the control and the NAB arms (71.4% vs. 53.3%; p = .45). Twenty-nine subjects experienced any AE, but none discontinued treatment. The 90-day mortality was not significantly different between the control (28.6%) and NAB arm (53.3%; p = .26). CONCLUSION: Adjunctive NAB was safe but did not improve overall response at 6 weeks. A different dosing schedule or nebulized liposomal amphotericin B may still need evaluation. More research is needed to explore other treatment options for PM.

Role of MRI in the Evaluation of Pulmonary Sequel Following COVID-19 Acute Respiratory Distress Syndrome (ARDS).

To evaluate the role of magnetic resonance imaging (MRI) chest as an alternative modality to CT chest for follow-up of patients recovered from severe COVID-19 acute respiratory distress syndrome (ARDS). A total of 25 subjects (16 [64%] men; mean age 54.84 years ± 12.35) who survived COVID-19 ARDS and fulfilled the inclusion criteria were enrolled prospectively. All the patients underwent CT and MRI chest (on the same day) at 6-weeks after discharge. MRI chest was acquired on 1.5T MRI using HASTE, BLADE, VIBE, STIR, and TRUFI sequences and evaluated for recognition of GGOs, consolidation, reticulations/septal thickening, parenchymal bands, and bronchial dilatation with CT chest as the gold standard. The differences were assessed by independent-sample t-test and Mann-Whitney U test. P-value of less than 0.05 was taken significant. There was a strong agreement (k = 0.8-1, P<0.01) between CT and MRI chest. On CT, the common manifestations were: GGOs (n=24, 96%), septal thickening/reticulations (n=24, 96%), bronchial dilatation (n=16, 64%), parenchymal bands (n=14, 56%), pleural thickening (n=8, 32%), consolidation (n=4, 16%) and crazy-paving (n=4, 16%). T2W HASTE, T2W BLADE, and T1 VIBE sequences showed 100% (95% CI, 40-100) sensitivity and 100% (95% CI, 3-100) specificity for detecting GGOs, septal thickening/reticulations, pleural thickening, consolidation, and crazy-paving. The overall sensitivity of MRI for detection of bronchial dilatation and parenchymal bands were 88.9% (95% CI, 77-100) and 92.9% (95% CI, 66-100), respectively; and specificity was 100% (95% CI, 29-100) for both findings. MRI chest, being radiation-free imaging modality can act as an alternative to CT chest in the evaluation of lung changes in patients recovered from COVID-19 pneumonia.

CT findings in sequel of COVID-19 pneumonia and its complications.

A significant number of patients after initial recovery from COVID-19 continue to experience lingering symptoms of the disease that may last for weeks or even months. Lungs being the most commonly affected organ by COVID-19, bear the major brunt of the disease and thus it is imperative to be aware of the evolution of the pulmonary parenchymal changes over time. CT chest is the imaging modality of choice to evaluate post-COVID lungs. Persistent ground-glass opacities, septal thickening, parenchymal bands, crazy-paving, traction bronchiectasis and consolidation constitute the commonly encountered imaging patterns seen on CT in post-COVID-19 lungs. Few vulnerable patients can develop lung fibrosis and show honeycombing on CT. Additionally, many complications like superadded infections (bacterial and fungal), pulmonary thromboembolism and pseudoaneurysm formation are also being reported. In the present pictorial review, we have tried to show the entire CT spectrum of sequelae of COVID-19 pneumonia and commonly associated infections and vascular complications.

Ultra-Low Dose CT Chest in Acute COVID-19 Pneumonia: A Pilot Study from India.

The rapid increase in the number of CT acquisitions during the COVID-19 pandemic raised concerns about increased radiation exposure to patients and the resultant radiation-induced health risks. It prompted researchers to explore newer CT techniques like ultra-low dose CT (ULDCT), which could improve patient safety. Our aim was to study the utility of ultra-low dose CT (ULDCT) chest in the evaluation of acute COVID-19 pneumonia with standard-dose CT (SDCT) chest as a reference standard. This was a prospective study approved by the institutional review board. 60 RT-PCR positive COVID-19 patients with valid indication for CT chest underwent SDCT and ULDCT. ULDCT and SDCT were compared in terms of objective (noise and signal-to-noise ratio) and subjective (noise, sharpness, artifacts and diagnostic confidence) image quality, various imaging patterns of COVID-19, CT severity score and effective radiation dose. The sensitivity, specificity, positive and negative predictive value, and diagnostic accuracy of ULDCT for detecting lung lesions were calculated by taking SDCT as a reference standard. The mean age of subjects was 47.2 ± 10.7 years, with 66.67% being men. 90% of ULDCT scans showed no/minimal noise and sharp images, while 93.33% had image quality of high diagnostic confidence. The major imaging findings detected by SDCT were GGOs (90%), consolidation (76.67%), septal thickening (60%), linear opacities (33.33%), crazy-paving pattern (33.33%), nodules (30%), pleural thickening (30%), lymphadenopathy (30%) and pleural effusion (23.33%). Sensitivity, specificity and diagnostic accuracy of ULDCT for detecting most of the imaging patterns were 100% (p < 0.001); except for GGOs (sensitivity: 92.59%, specificity: 100%, diagnostic accuracy: 93.33%), consolidation (sensitivity: 100%, specificity: 71.43%, diagnostic accuracy: 93.33%) and linear opacity (sensitivity: 90.00%, specificity: 100%, diagnostic accuracy: 96.67%). CT severity score (range: 15-25) showed 100% concordance on SDCT and ULDCT, while effective radiation dose was 4.93 ± 1.11 mSv and 0.26 ± 0.024 mSv, respectively. A dose reduction of 94.38 ± 1.7% was achieved with ULDCT. Compared to SDCT, ULDCT chest yielded images of reasonable and comparable diagnostic quality with the advantage of significantly reduced radiation dose; thus, it can be a good alternative to SDCT in the evaluation of COVID-19 pneumonia.

Radiation Exposure and Lifetime Attributable Risk of Cancer Incidence and Mortality from Low- and Standard-Dose CT Chest: Implications for COVID-19 Pneumonia Subjects.

Since the novel coronavirus disease 2019 (COVID-19) outbreak, there has been an unprecedented increase in the acquisition of chest computed tomography (CT) scans. Nearly 616 million people have been infected by COVID-19 worldwide to date, of whom many were subjected to CT scanning. CT exposes the patients to hazardous ionizing radiation, which can damage the genetic material in the cells, leading to stochastic health effects in the form of heritable genetic mutations and increased cancer risk. These probabilistic, long-term carcinogenic effects of radiation can be seen over a lifetime and may sometimes take several decades to manifest. This review briefly describes what is known about the health effects of radiation, the lowest dose for which there exists compelling evidence about increased radiation-induced cancer risk and the evidence regarding this risk at typical CT doses. The lifetime attributable risk (LAR) of cancer from low- and standard-dose chest CT scans performed in COVID-19 subjects is also discussed along with the projected number of future cancers that could be related to chest CT scans performed during the COVID-19 pandemic. The LAR of cancer Incidence from chest CT has also been compared with those from other radiation sources, daily life risks and lifetime baseline risk.

A 63-year-old man with hypoxemia and shock after initial recovery from COVID-19 pneumonia.

A 63-year-old man presented with fever and breathlessness during the coronavirus disease 2019 (COVID-19) pandemic. He was diagnosed to have severe COVID-19 pneumonia. He was treated with oxygen, noninvasive ventilation, and glucocorticoids. He improved over 5 weeks and was shifted out of the intensive care unit. Subsequently, he experienced worsening during hospitalization with refractory hypoxemia and shock and finally succumbed to his illness. An autopsy was performed. Herein, we have presented a clinical discussion on the possible causes of the patient's fatal outcome followed by the autopsy findings.

Definition, diagnosis, and management of COVID-19-associated pulmonary mucormycosis: Delphi consensus statement from the Fungal Infection Study Forum and Academy of Pulmonary Sciences, India.

COVID-19-associated pulmonary mucormycosis (CAPM) remains an underdiagnosed entity. Using a modified Delphi method, we have formulated a consensus statement for the diagnosis and management of CAPM. We selected 26 experts from various disciplines who are involved in managing CAPM. Three rounds of the Delphi process were held to reach consensus (≥70% agreement or disagreement) or dissensus. A consensus was achieved for 84 of the 89 statements. Pulmonary mucormycosis occurring within 3 months of COVID-19 diagnosis was labelled CAPM and classified further as proven, probable, and possible. We recommend flexible bronchoscopy to enable early diagnosis. The experts proposed definitions to categorise dual infections with aspergillosis and mucormycosis in patients with COVID-19. We recommend liposomal amphotericin B (5 mg/kg per day) and early surgery as central to the management of mucormycosis in patients with COVID-19. We recommend response assessment at 4-6 weeks using clinical and imaging parameters. Posaconazole or isavuconazole was recommended as maintenance therapy following initial response, but no consensus was reached for the duration of treatment. In patients with stable or progressive disease, the experts recommended salvage therapy with posaconazole or isavuconazole. CAPM is a rare but under-reported complication of COVID-19. Although we have proposed recommendations for defining, diagnosing, and managing CAPM, more extensive research is required.

The Integral Role of Radiology in the Diagnosis and Management of COVID-19-Associated Mucormycosis Infections.

Recently, there has been a sudden surge in COVID-19-associated mucormycosis (CAM) infections. Rhino-oculo-cerebral and pulmonary mucormycosis are the two most common forms of CAM. Radiology plays an integral role in the management of CAM. Computed tomography (CT) determines gross bony and soft tissue involvement in COVID-19-associated rhino-oculo-cerebral mucormycosis, whereas magnetic resonance imaging helps in evaluation of the orbital and intracranial extension. Paranasal sinus soft tissue with extrasinus infiltration with or without bony destruction is suggestive of COVID-19-associated rhino-oculo-cerebral mucormycosis. High-resolution CT chest scan has shown to be helpful in the diagnosis of COVID-19-associated pulmonary mucormycosis. Consolidation and cavitation are the most common imaging features. Other CT abnormalities include the reverse-halo sign, pleural effusion, ground-glass opacities, pneumothorax, nodules, and pulmonary embolism. A high index of suspicion with appropriate imaging findings can lead to the early diagnosis of CAM and timely initiation of antifungal treatment and/or surgical debridement, which can be lifesaving.

Mortality Prediction of COVID-19 Patients at Intensive Care Unit Admission.

Background Coronavirus-2019 (COVID-19) patients admitted to the intensive care unit (ICU) have mortality rates between 30%-50%. Identifying patient factors associated with mortality can help identify critical patients early and treat them accordingly. Patients and methods In this retrospective study, the records of patients admitted to the COVID-19 ICU in a single tertiary care hospital from April 2020 to September 2020 were analysed. The clinical and laboratory parameters between patients who were discharged from the hospital (survival cohort) and those who died in the hospital (mortality cohort) were compared. A multivariate logistic regression model was constructed to identify parameters associated with mortality.  Results A total of 147 patients were included in the study. The age of the patients was 55 (45, 64), median (IQR), years. At admission, 23 (16%) patients were on mechanical ventilation and 73 (50%) were on non-invasive ventilation. Sixty patients (40%, 95% CI: 32.8 to 49.2%) had died. Patients who died had a higher Charlson comorbidity index (CCI): 3 (2, 4) vs. 2 (1, 3), p = 0.0019, and a higher admission sequential organ failure assessment (SOFA) score: 5 (4, 7) vs. 4 (3, 4), p < 0.001. Serum urea, serum creatinine, neutrophils on differential leukocyte count, neutrophil to lymphocyte ratio (N/L ratio), D-dimer, serum lactate dehydrogenase (LDH), and C-reactive protein were higher in the mortality cohort. The ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, platelet count, lymphocytes on differential leukocyte count, and absolute lymphocyte count was lower in the mortality cohort. The parameters and cut-off values used for the multivariate logistic regression model included CCI > 2, SOFA score > 4, D-dimer > 1346 ng/mL, LDH > 514 U/L and N/L ratio > 27. The final model had an area under the curve of 0.876 (95% CI: 0.812 to 0.925), p < 0.001 with an accuracy of 78%. All five parameters were found to be independently associated with mortality.  Conclusions CCI, SOFA score, D-dimer, LDH, and N/L ratio are independently associated with mortality. A model incorporating the combination of these clinical and laboratory parameters at admission can predict COVID-19 ICU mortality with good accuracy.

Imaging of Pulmonary Superinfections and Co-Infections in COVID-19.

New challenges in imaging and management of COVID-19 pneumonia emerge as the pandemic continues across the globe. These arise not only due to the COVID-19 pneumonia but also related to various superinfections and co-infections. Limited use of bronchoscopic and other aerosol generating procedures to obtain representative lower respiratory samples from these patient groups for accurate identification of organism, increases the responsibility of radiologists in suggesting the most likely cause of secondary infection. Imaging features of many of these infections overlap with features of COVID-19 pneumonia. In this review, we highlight imaging findings that can aid in the diagnosis of superinfections and co-infections in patients with COVID-19 pneumonia, and also help in predicting the likely causative organism.

The Conundrum of 'Long-COVID-19': A Narrative Review.

COVID-19 is an ongoing pandemic with many challenges that are now extending to its intriguing long-term sequel. 'Long-COVID-19' is a term given to the lingering or protracted illness that patients of COVID-19 continue to experience even in their post-recovery phase. It is also being called 'post-acute COVID-19', 'ongoing symptomatic COVID-19', 'chronic COVID-19', 'post COVID-19 syndrome', and 'long-haul COVID-19'. Fatigue, dyspnea, cough, headache, brain fog, anosmia, and dysgeusia are common symptoms seen in Long-COVID-19, but more varied and debilitating injuries involving pulmonary, cardiovascular, cutaneous, musculoskeletal and neuropsychiatric systems are also being reported. With the data on Long-COVID-19 still emerging, the present review aims to highlight its epidemiology, protean clinical manifestations, risk predictors, and management strategies. With the re-emergence of new waves of SARS-CoV-2 infection, Long-COVID-19 is expected to produce another public health crisis on the heels of current pandemic. Thus, it becomes imperative to emphasize this condition and disseminate its awareness to medical professionals, patients, the public, and policymakers alike to prepare and augment health care facilities for continued surveillance of these patients. Further research comprising cataloging of symptoms, longer-ranging observational studies, and clinical trials are necessary to evaluate long-term consequences of COVID-19, and it warrants setting-up of dedicated, post-COVID care, multi-disciplinary clinics, and rehabilitation centers.

Computed tomography chest in COVID-19: When & why?

Computed tomography (CT) of the chest plays an important role in the diagnosis and management of coronavirus disease 2019 (COVID-19), but it should not be used indiscriminately. This review provides indications of CT chest in COVID-19 suspect, positive and recovered patients based on the current scientific evidence and our personal experience. CT chest is not indicated as a routine screening modality due to its poor sensitivity and specificity. However, it is useful in a small subset of COVID-19 suspects who test negative on reverse transcription-polymerase chain reaction (RT-PCR) with normal/indeterminate chest X-ray (CXR) but have moderate-to-severe respiratory symptoms and high index of clinical suspicion. CT chest is not indicated in every RT-PCR-positive patient and should be done only in specific clinical scenarios, where it is expected to significantly contribute in the clinical management such as COVID-19 patients showing unexplained clinical deterioration and/or where other concurrent lung pathology or pulmonary thromboembolism needs exclusion. Serial CXR and point-of-care ultrasound are usually sufficient to evaluate the progression of COVID-19 pneumonia. CT chest is also indicated in COVID-19-positive patients with associated co-morbidities (age >65 yr, diabetes, hypertension, obesity, cardiovascular disease, chronic respiratory disease, immune-compromise, etc.) who, despite having mild symptoms and normal/indeterminate CXR, record oxygen saturation of <93 per cent at rest while breathing room air or de-saturate on six-minute walk test. Finally, CT chest plays a crucial role to rule out lung fibrosis in patients recovered from COVID-19 infection who present with hypoxia/impaired lung function on follow up. In conclusion, though CT chest is an indispensable diagnostic tool in COVID-19, it should be used judiciously and only when specifically indicated.

Diagnostic accuracy of CT and radiographic findings for novel coronavirus 2019 pneumonia: Systematic review and meta-analysis.

PURPOSE: To evaluate pooled prevalence, sensitivity, and specificity of chest computed tomography (CT) and radiographic findings for novel coronavirus-2019 (COVID-19) pneumonia. METHODS: We performed systematic literature search in PubMed and Embase to identify articles reporting baseline imaging findings of COVID-19 pneumonia. The quality of the articles was assessed using NIH quality assessment tool for case series studies. The pooled prevalence, sensitivity, specificity, and diagnostic odds ratio of imaging findings were calculated. RESULTS: Fifty-six studies (6007 patients, age, 2.1-70 years, 2887 females, 5762 CT, 396 radiographs,) were included. The mean interval between onset of symptoms and CT acquisition was 1-8 days. On CT, the pooled prevalence of ground glass opacities (GGO), GGO plus consolidation, and consolidation only was 66.9% (95% CI 60.8-72.4%), 44.9% (38.7-51.3%), and 32.1 (23.6-41.9%) respectively. Pooled sensitivity and specificity of GGO on CT was 73% (71%-80%) and 61% (41%-78%), respectively. For GGO plus consolidation and consolidation only, the pooled sensitivities/ specificities were 58% (48%-68%)/ 58% (41%-73%) and 49% (20%-78%)/ 56% (30%-78%), respectively. The pooled prevalence of GGO and consolidation on chest radiograph was 38.7% (22.2%-58.3%) and 46.9% (29.7%-64.9%), respectively. The diagnostic accuracy of radiographic findings could not be assessed due to small number of studies. CONCLUSION: GGO on CT has the highest diagnostic performance for COVID-19 pneumonia, followed by GGO plus consolidation and consolidation only. However, the moderate to low sensitivity and specificity suggest that CT should not be used as the primary tool for diagnosis. Chest radiographic abnormalities are seen in half of the patients.

Unraveling the mystery of Covid-19 cytokine storm: From skin to organ systems.

COVID-19 is a global pandemic that emerged from Wuhan, China. Besides pneumonia and acute respiratory distress syndrome, the disease leads to multisystem involvement in the form of myocarditis, arrhythmias, cardiac arrest, gastrointestinal symptoms, hypoxemic brain injury, acute liver, and renal function impairment. There are also reports of cutaneous lesions in form of urticarial and maculopapular rashes, chilblain like fingers and toes (covid feet), livedoid vasculopathy, and chicken-pox like or varicelliform vesicles. Clinically, many of these skin lesions are likely secondary to occlusion of small to medium blood vessels due to microthrombi formation or due to viral laden antigen-antibody immune complexes; and same explanation may hold true for possible hypoxemic injury simultaneously occurring in other vital organs like lungs, heart, brain, and kidneys. The histopathology, immunoflorescence and RT-PCR analysis of skin biopsies can provide useful insights for ascertaining the pathogenesis of this complex viral syndrome. Apparently, it is interplay of disarmed cellular immunity and over-activated humoral immunity that culminates in end-organ changes. The morbidity and mortality can be significantly reduced by upgrading the cellular immunity and downgrading the humoral response; along with prevention of hypoxemic and reperfusion injuries by using antivirals, immunomodulators, antioxidants, anti-platelets, and anticoagulants in judicious and phased manner.