Utility of itraconazole and terbinafine in mucormycosis: a proof-of-concept analysis.

An epidemic of mucormycosis followed the second wave of COVID 19 in the state of Uttar Pradesh, India in May 2021. This epidemic, however, had additional challenges to offer in the form of acute shortage of all forms of amphotericin B, posaconazole and isavuconazole. It was, therefore, planned to assess the trends in minimum inhibitory concentration (MIC) of antifungal agents, viz itraconazole and terbinafine, and provide a template for personalized therapy to see whether the results could be translated clinically. This is an observational, single-center study. Samples comprising nasal swab, nasal and paranasal sinus tissue, brain tissue, brain abscess and orbital content, derived from 322 patients from northern India with mucormycosis, of whom 215 were male and 107 were female, were used for analysis. Cultures were identified both by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and conventional methods of identification. Antifungal susceptibility was done for amphotericin B, posaconazole, isavuconazole, itraconazole and terbinafine as per Clinical Laboratory Standard Institute M38-A2. The outcome was identification of the species of mucormycosis and susceptibility to itraconazole and terbinafine besides other primary antifungal agents. Patients or the public were not involved in the design, or conduct, or reporting or in the dissemination plans of our research. Of 322 patients, 203 were culture-positive, of whom 173 were positive by both MALDI-TOF and conventional methods of identification. Final antifungal susceptibility testing was available for 150 patients. The most common Mucorales found to cause this epidemic was Rhizopus oryzae, followed by R. microsporus Amphotericin B, posaconazole and isavuconazole had low MIC values in 98.8% of all Mucorales identified. The MIC of itraconazole was species-dependent. 97.7% of Roryzae had MIC ≤2 µg/mL. However, only 36.5% of Rmicrosporus had MIC ≤2 µg/mL. For terbinafine, 85.2% of R. microsporus had MIC ≤2 µg/mL. We conclude that identification at the species level is required as antifungal susceptibilities seem to be species-dependent. Assessment of the efficacy of itraconazole and terbinafine warrants further studies with clinical assessment and therapeutic drug monitoring as they seem to be potential candidates especially when the primary agents are not available.

Severe COVID-19-associated hyperinflammatory syndrome versus classic hemophagocytic lymphohistiocytosis: similarities, differences, and the way forward.

The hyperinflammatory immune response in severe COVID-19 infection shares features with secondary hemophagocytic lymphohistiocytosis (sHLH) in the form of fever, cytopenia, elevated inflammatory markers, and high mortality. There are contrasting opinions regarding utility of HLH 2004 or HScore in the diagnosis of severe COVID-19-related hyperinflammatory syndrome (COVID-HIS). This was a retrospective study of 47 patients of severe COVID-19 infection, suspected to have COVID-HIS and 22 patients of sHLH to other illnesses, to evaluate the diagnostic utility and limitations of HLH 2004 and/or HScore in context to COVID-HIS and to also evaluate the utility of Temple criteria for predicting severity and outcome in COVID-HIS. Clinical findings, hematological, and biochemical parameters along with the predictor of mortality were compared between two groups. Only 6.4% (3/47) of cases fulfilled ≥5/8 HLH 2004 criteria and only 40.52% (19/47) of patients showed HScore >169 in COVID-HIS group. 65.9% (31/47) satisfied the Temple criteria in COVID-HIS as compared with 40.9% (9/22) in the non-COVID group (p = 0.04). Serum ferritin (p = 0.02), lactate dehydrogenase (p = 0.02), direct bilirubin (p = 0.02), and C-reactive protein (p = 0.03) were associated with mortality in COVID-HIS. Both HScore and HLH-2004 criteria perform poorly for identifying COVID-HIS. Presence of bone marrow hemophagocytosis may help to identify about one-third of COVID-HIS missed by the Temple Criteria.

T-cell dysfunction as a potential contributing factor in post-COVID-19 mucormycosis.

BACKGROUND: The second wave of COVID-19 in India was followed by large number of mucormycosis cases. Indiscriminate use of immunosuppressive drugs, underlying diseases such as diabetes, cancers, or autoimmune diseases was thought to be the cause. However, the mortality was not as high as that seen in non-COVID mucormycosis. OBJECTIVE: To study the detailed characteristics of T-cells for evaluating the underlying differences in the T-cell immune dysfunction in post-COVID and non-COVID mucor patients. MATERIAL AND METHOD: The study included histopathologically confirmed cases of mucor (13 post-COVID, 13 non-COVID) and 15 healthy individuals (HI). Expression of T-cell activation (CD44, HLADR, CD69, CD38) and exhaustion (CTLA, PD-1, LAG-3 and TIM-3) markers was evaluated by flow cytometry. RESULTS: All cases showed significant depletion of T-cells compared to HI. Both post-COVID and non-COVID groups showed increased activation and exhaustion as compared to HI. Non-COVID mucor group showed significant activation of CD4+ T cells for HLADR and CD38 (p = .025, p = .054) and marked T-cell exhaustion in form of expression of LAG-3 on both CD4+ T and CD8+ T cells in comparison with post-COVID patients (p = .011, p = .036). Additionally, co-expression of PD-1 & LAG-3 and LAG-3 & TIM-3 on CD8+ T cells was statistically significant in non-COVID mucor patients (p = .016, p = .027). CONCLUSION: Immunosuppression in non-COVID mucor showed pronounced exhaustion of T-cells in comparison to post-COVID mucor cases implicating T-cell immune dysfunction is much more severe in non-COVID mucor which are in a state of continuous activation followed by extreme exhaustion leading to poorer outcome.

COVID-19 associated mucormycosis: Staging and management recommendations (Report of a multi-disciplinary expert committee).

Even before the onslaught of COVID-19 pandemic could settle, the unprecedented rise in cases with COVID-19 associated mucormycosis pushed the medical health to the fringe. Hyperglycaemia and corticosteroids appear to be the most consistent associations leading to the commonest manifestation of mucormycosis, Rhino-Orbito-Cerebral Mucormycosis. To address challenges right from categorisation and staging of the disease to the management of relentless progression, a multi-disciplinary expert committee was formed to handle the task in an evidence-based format to enforce best practices. The report of the committee on one hand attempts to succinctly present the currently available evidence while at the other also attempts to bridge the evidence-deficient gaps with the specialty-specific virtuosity of experts.

COVID-19-associated Guillain-Barre syndrome: Postinfectious alone or neuroinvasive too?

Coronavirus disease 2019 (COVID-19) has been shown to be associated with a lot of neurological complications, of whom Guillain-Barre syndrome (GBS) is an important post-infectious consequentiality. More than 220 patients with GBS have been reported thus far. We intend to share our experience with five patients of GBS where one of them had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the cerebrospinal fluid (CSF). This is the first-ever report demonstrating the presence of SARS-CoV-2 in the CSF of an adult patient; a similar occurrence has recently been described in a pediatric patient. We wish to emphasize the fact that commonly GBS occurs as a result of a post-infectious process but in a few cases where the symptoms of COVID-19 and GBS occur concurrently, corresponding to the viremic phase, separate pathogenesis needs to be thought of. This para-infectious nature is exemplified by the presence of virus in the cerebrospinal fluid of one of our patients. We review the neuroinvasive potential of SARS-Cov-2 in this regard and draw parallels with Cytomegalovirus, Zika virus, and Human Immunodeficiency virus-associated occurrences of GBS.

Hemophagocytic histiocytosis in severe SARS-CoV-2 infection: A bone marrow study.

INTRODUCTION: The clinical and laboratory features of severe COVID-19 infection overlap with those of hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory disorder often associated with several viral infections. The clinical syndrome of HLH encompasses fever, organomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia, raised transaminases, hypofibrinogenemia, absent natural killer (NK) cell activity, increased soluble CD25 and hemophagocytic lymphohistiocytosis in bone marrow, spleen, and lymph nodes. METHODS: We analyzed clinicopathological and laboratory features of thirteen patients with severe COVID-19 infection suspected to have HLH and found to have hemophagocytic histiocytosis on bone marrow examination (BME). RESULTS: Five of thirteen (38.46%) patients fulfilled five of eight HLH 2004 criteria and/or had a H-score ≥169. Three (23.08%) satisfied four of eight and remainder five (38.46%) satisfied three of eight HLH 2004 criteria. Fever, raised serum ferritin (13/13, 100%), transaminases (9/13, 69.23%), triglycerides (4/13, 30.76%), cytopenias (5/13, 38.46%), hypofibrinogenemia (2/13, 15.38%), and organomegaly (1/13, 7.69%) were observed in our patients. BME showed hemophagocytic histiocytosis without lymphocytosis in all. Contrary to HLH, lymphocytopenia (11/13, 84.61%), leukocytosis (7/13, 53.84%), neutrophilia (7/13, 53.84%), and hyperfibrinogenemia (7/13, 53.84%) were observed. Serum CRP, LDH, and plasma D-dimer were elevated in all, while serum albumin was decreased in 12 of 13 (92.3%) patients. Five patients recovered with high-dose pulsed corticosteroid therapy. CONCLUSION: The immune response associated with severe COVID-19 infection is similar to HLH with few differences. HLH should be suspected in severe COVID-19 infection although all patients may not fulfill required HLH diagnostic criteria. BME should be done in suspected cases so that appropriate therapy may be initiated early.

A Phase II Safety and Efficacy Study on Prognosis of Moderate Pneumonia in Coronavirus Disease 2019 Patients With Regular Intravenous Immunoglobulin Therapy.

BACKGROUND: Currently, there is no specific drug for the treatment of coronavirus disease 2019 (COVID-19). Therapeutic benefits of intravenous immunoglobulin (IVIG) have been demonstrated in wide range of diseases. The present study is conducted to evaluate the safety and efficacy of IVIG in the treatment of COVID-19 patients with moderate pneumonia. METHODS: An open-label, multicenter, comparative, randomized study was conducted on COVID-19 patients with moderate pneumonia. One hundred eligible patients were randomized in 1:1 ratio either to receive IVIG + standard of care (SOC) or SOC. RESULTS: Duration of hospital stay was significantly shorter in the IVIG group compared with that of SOC alone (7.7 vs 17.5 days). Duration for normalization of body temperature, oxygen saturation, and mechanical ventilation were significantly shorter in IVIG compared with SOC. Percentages of patients on mechanical ventilation in 2 groups were not significantly different (24% vs 38%). Median time to reverse-transcription polymerase chain reaction negativity was significantly shorter with IVIG than SOC (7 vs 18 days). There were only mild to moderate adverse events in both groups except for 1 patient (2%), who died in SOC. CONCLUSIONS: Intravenous immunoglobulin was safe and efficacious as an adjuvant with other antiviral drugs in the treatment of COVID-19.

Complicated case of COVID-19 disease with overlapping features of thrombotic thrombocytopenic purpura and haemophagocytic lymphohistiocytosis.

Haemophagocytic lymphohistiocytosis has been reported as an uncommon complication of severe COVID-19 disease while thrombotic thrombocytopenic purpura has been rarely reported. Here, we are reporting a 21-year-old man who developed a combination of these complications during the hospital stay in the post-COVID-19 recovery period. He presented with fever and bilateral COVID-19-related pneumonia requiring invasive ventilation. His hospital course was complicated by the development of pneumothorax, ventilator-associated pneumonia, thrombotic thrombocytopenic purpura and haemophagocytic lymphohistiocytosis. He received remdesivir, IVIG, steroid, fresh frozen plasma and supportive care but had a fatal outcome.

Current Insight into the Novel Coronavirus Disease 2019 (COVID-19)

SARS-CoV-2 is a novel strain of coronavirus that has not been previously identified in humans. It has been declared a pandemic and has infected at least 1,844,683 individuals and caused 117,021 deaths as of 14th April 2020. Transmission among humans occurs via close contact with an infected individual that produces respiratory droplets. Patients have been shown to undergo acute respiratory distress syndrome, which is defined as cytokine storm. The diagnosis relies on detection of nucleic acid, IgG/IgM antibodies, and a chest radiograph of the suspected individuals. The genome of SARS-CoV-2 is similar to other coronaviruses that comprise of ten open reading frames (ORFs). SARS-CoV-2 spike protein exhibits higher affinity to ACE2 receptor as compared with SARS-CoV. Repurposing drugs like favipiravir, remdesivir, chloroquine, and TMPRSS2 protease inhibitors have been shown to be effective for the treatment of COVID-19. Personal protective measures should be followed to prevent SARS-CoV-2 infection. In addition, a clinical trial of SARS-CoV-2 vaccine, mRNA-1273, has been started. This chapter provides a glimpse of advancements made in the area of SARS-CoV-2 infection by proving recent clinical and research trials in the field.

COVID-19: benefits and risks of passive immunotherapeutics.

Passive immunotherapeutics (PITs), including convalescent plasma, serum, or hyperimmune immunoglobulin, have been of clinical importance during sudden outbreaks since the early twentieth century for the treatment of viral diseases such as severe acute respiratory syndrome (SARS), middle east respiratory syndrome (MERS) and swine flu (H1N1). With the recent SARS-CoV-2 pandemic, wherein effective antivirals and vaccines are still lacking, an interest in convalescent plasma therapy as a lifesaving option has resurfaced due to its capacity for antigenic neutralization and reducing viremia. This review summarizes convalescent blood products (CBPs) in terms of current technologies and the shortcomings related to the collection, manufacture, pathogen inactivation, and banking of CBPs, with a specific focus on their plausible applications, benefits, and risks in the COVID-19 pandemic.