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Novel Treatment of Infant With COVID-19 With the Sialidase Fusion Protein, DAS181

Danziger-Isakov, Lara MD*; Khalil, Nadim MD*; Divanovic, Allison MD*; Frenck, Robert MD*; Grimley, Michael MD*; Iliopoulos, Ilias MD*; Marsh, Rebecca MD*; Paulsen, Grant MD*; Phillips, Christine L. MD*; Schulert, Grant MD*; Spearman, Paul MD*; Blum, Samantha BSN*; Hui-Chin Ho, Jennifer MD

Author Information
The Pediatric Infectious Disease Journal: June 2021 - Volume 40 - Issue 6 - p e234-e235
doi: 10.1097/INF.0000000000003122
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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly emerging viral pathogen that causes respiratory failure and death.1 Between April and November 2020, in the United States, SARS-CoV-2 has caused 772,369 cases and 117 deaths in children younger than 18 years of age.2 However, there are currently no US Food and Drug Administration-approved (FDA) drugs for the treatment of Coronavirus disease 2019 (COVID-19) in patients less than 12 years of age.3 Remdesivir, now available approved by FDA for older children and through the FDA Emergency Use Authorization for children less than 12 years of age,3 could not be obtained for our patient at the time of illness. In this report, we discuss the use of DAS181 (Ansun BioPharma, San Diego, CA), a new nebulized antiviral agent, to treat a patient with COVID-19.

CASE

In May 2020, a hospitalized 10-month-old female with 22q11.2 deletion syndrome, double outlet right ventricle and ventricular septal defect, and tracheomalacia with severe compression of bilateral mainstem bronchi, developed acute respiratory distress. She had been hospitalized for a biventricular repair, closure of ventricular septal defect and right ventricle-pulmonary artery conduit placement (Rastelli procedure), performed 80 days prior. Because of worsening respiratory status and the need for further supportive care, she was transferred to the cardiac intensive care unit (CICU). In the CICU, she had severe increased work of breathing, hypercarbia (venous pCO2 86 mm Hg) and decreased oxygen saturation (SaO2 58%). Chest radiograph showed diffuse pulmonary airspace opacities without a focal consolidation (Fig. 1). Respiratory support was administered via high flow nasal cannula at a rate of 12 L of oxygen per minute (Lpm), 100% FiO2. She was febrile with temperature of 38.8°C and started empirically on intravenous cefepime.

FIGURE 1.
FIGURE 1.:
Increased bilateral pulmonary airspace opacities atelectasis on chest radiograph at time of respiratory distress (A) compared with previous radiograph obtained a month prior (B).

At the time of transfer to the CICU and respiratory decline, SARS-CoV-2 polymerase chain reaction (PCR) (DiaSorin Molecular assay, Cypress, CA) was positive from nasopharyngeal swab. Testing for other viral respiratory pathogens (including influenza, parainfluenza, human metapneumovirus, respiratory syncytial virus and enterovirus) was negative. The patient did not have any evidence of a systemic inflammatory process: procalcitonin 0.23 ng/mL, C-reactive protein < 0.40 mg/dL and ferritin 93.9 (reference range 15–450 ng/mL). While she required supplemental oxygen, treatment with remdesivir could not be initiated, at that time, due to limited drug availability. At time of the case, treatment recommendations did not support the administration of systemic corticosteroid. As the patient’s respiratory status was not improving with supportive care, the FDA granted humanitarian use approval for administration of DAS181, a sialidase catalytic domain/amphiregulin glycosaminoglycan binding sequence fusion protein. Three days after the diagnosis of COVID-19 was made, the infant began treatment of 2.5 mg of DAS181 mixed in 2.11 mL of sterile water via Aerogen Solo nebulizer twice daily for 5 days (10 doses). Within 5 days of treatment initiation, the patient’s tachypnea had resolved (respiratory rate decreased from 52 to 21 breaths per minute) and her requirement for supplemental oxygen decreased from 12 Lpm to her baseline of 0.5 Lpm. While the initial PCR for SARS-CoV-2 was positive, subsequent PCR testing on days 2, 4 and 6 following initiation of DAS181 therapy were negative. The child tolerated DAS181 without any complications or side effects. Close monitoring of biochemical profile was conducted surrounding DAS181 treatment. Laboratory results demonstrated mild elevation of alkaline phosphatase to 366 (ref range 107–333 unit/L). Aspartate aminotransferase, alanine aminotransferase, creatinine and complete blood count remained normal in the week following initiation of DAS181 therapy. She was discharged home 8 days after initiation of DAS181 treatment.

Five days following discharge home, the patient was seen in outpatient clinic and appeared to be well. She did not have any respiratory or systemic symptoms suggestive of recurrence of disease or multisystem inflammatory syndrome in children (MIS-C). However, for unclear reasons, the following day, the child had a cardiac arrest and could not be resuscitated. The family declined the request for autopsy. As the child had been at her baseline during the prior week, the cause of death was presumptively attributed to her underlying cardiac disease.

DISCUSSION

We describe the first pediatric patient with COVID-19 and respiratory distress treated with the novel antiviral DAS181. Currently, there are no FDA-approved therapeutic agents for the treatment of COVID-19 in pediatric patients less than 12 years of age.4

Due to the patient’s underlying medical conditions that could predispose her to worsening respiratory infection and lack of improvement with supportive care, treatment with DAS181 was pursued. DAS181 cleaves sialic acids from the host cell surface. The in vitro implications of sialic acid removal can be both antiviral inhibition of entry as well as immunomodulatory effects on T cells and cytokines.5,6 Sialic acid binding is a key step in the entry process of some coronaviruses including OC43 and MERS and may play a role in the lifecycle of SARS-CoV-2.7,8 DAS181 was previously reported to be beneficial in treating immunocompromised pediatric patients with moderate respiratory distress secondary to parainfluenza infection.6 In adults, DAS181 has been used to treat parainfluenza virus infections and pneumonia in hematopoietic stem cell transplant recipients9 and lung transplant recipients.10 Our patient tolerated the treatment and did not have any side effects or complication secondary to therapy. Similar to previous reports,9 mild and asymptomatic elevation of alkaline phosphatase was noted. Previously, treatment with DAS181 had been well tolerated and with mild side effects reported.6,9

The antiviral agent remdesivir is available through the FDA Emergency Use Authorization for the treatment of COVID-19 in pediatric patients less than 12 years of age and with severe disease.4 However, due to limited availability of the drug at time of the patient’s illness, remdesivir was not administered. Additionally, our patient did not meet the diagnosis of multisystem inflammatory syndrome in children (MIS-C) as she did not have a preceding illness consistent with COVID-19 in the prior month and had normal creatinine phosphokinase (CPK), troponin and fibrinogen levels.11

This is the first case of a pediatric patient with COVID-19 treated with nebulized DAS181. Our patient tolerated therapy and demonstrated clinical improvement of her respiratory distress shortly following the initiation of therapy. Unfortunately, our patient died 2 weeks after DAS181 therapy at home, suspected to be secondary to cardiac arrest and her underlying cardiac disease. DAS181 has been administered to over 850 patients, and there have been no reports of treatment-related cardiac events.12 Previous pharmacodynamics data demonstrated that nebulized DAS181 up to 10 doses was undetectable in the circulation on day 14.

As the number of COVID-19 cases increase worldwide, DAS181 appears to be a promising agent in the treatment of COVID-19 without systemic inflammation in immunocompetent pediatric patients. Prospective, randomized phase III clinical trials assessing the efficacy of DAS181 in treating immunocompromised subjects with lower respiratory tract infection caused by parainfluenza viruses and a phase 2 substudy of severe COVID-19 (caused by SARS-CoV-2)13 are currently underway and will be essential to determine the effectiveness and safety of this potentially life-saving treatment.

REFERENCES

1. Centers for Disease Control and Prevention (CDC)Coronavirus Disease 2019 (COVID-19). Published February 11, 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html. Accessed August 24, 2020.
2. Centers for Disease Control and Prevention (CDC)Demographic Trends of COVID-19 cases and deaths in the US reported to CDC. 2020. Available at: https://www.cdc.gov/covid-data-tracker/#demographics. Accessed November 17, 2020.
3. National Institutes of Health (NIH)Antiviral Therapy. COVID-19 Treatment Guidelines. 2020. Available at: https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/. Accessed November 17, 2020.
4. National Institutes of Health (NIH).Special Considerations in Children. COVID-19 Treatment Guidelines. 2020. Available at: https://www.covid19treatmentguidelines.nih.gov/special-populations/children/. Accessed November 17, 2020.
5. Amerra, Inc./Ansun Biopharma, Inc. DAS181 Mechanism of Action. 2019. Available at: https://www.youtube.com/watch?v=y_3kUnw5EF&feature=emb_title. Accessed August 21, 2020.
6. Waghmare A, Wagner T, Andrews R, et al. Successful treatment of parainfluenza virus respiratory tract infection with DAS181 in 4 immunocompromised children. J Pediatric Infect Dis Soc. 2015;4:114–118.
7. Qing E, Hantak M, Perlman S, et al. Distinct roles for sialoside and protein receptors in Coronavirus infection. mBio. 2020;11::e02764-19.
8. Tortorici MA, Walls AC, Lang Y, et al. Structural basis for human Coronavirus attachment to sialic acid receptors. Nat Struct Mol Biol. 2019;26:481–489.
9. Salvatore M, Satlin MJ, Jacobs SE, et al. DAS181 for treatment of parainfluenza virus infections in hematopoietic stem cell transplant recipients at a single center. Biol Blood Marrow Transplant. 2016;22:965–970.
10. Drozd DR, Limaye AP, Moss RB, et al. DAS181 treatment of severe parainfluenza type 3 pneumonia in a lung transplant recipient. Transpl Infect Dis. 2013;15:E28–E32.
11. Centers for Disease Control and Prevention (CDC).Multisystem Inflammatory Syndrome in Children (MIS-C)Centers for Disease Control and PreventionPublished February 11, 2020. Available at: https://www.cdc.gov/mis-c/. Accessed August 24, 2020.
12. Moss RB, Hansen C, Sanders RL, et al. A phase II study of DAS181, a novel host directed antiviral for the treatment of influenza infection. J Infect Dis. 2012;206:1844–1851.
13. Ansun Biopharma, Inc. A Phase III Randomized Placebo-Controlled Study to Examine the Efficacy and Safety of DAS181 for the Treatment of Lower Respiratory Tract Parainfluenza Infection in Immunocompromised Subjects. 2020. clinicaltrials.gov; Available at: https://clinicaltrials.gov/ct2/show/NCT03808922. Accessed August 21, 2020.
Keywords:

SARS-CoV-2; pediatric; infectious diseases; pharmacology

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