April 1, 2020

Outcomes of patients with severe COVID-19 treated with high-dose intravenous immunoglobulin and outcomes of patients with severe COVID-19 from Seattle

By Denise Baez

NEW YORK -- April 1, 2020 -- Today’s DG Alert covers high-dose intravenous immunoglobulin as a therapeutic option for deteriorating patients with coronavirus disease 2019 (COVID-19), and the outcomes of patients with severe COVID-19 from Seattle, Washington. 

A case series published in Open Forum Infectious Diseases describes the outcomes of 3 patients with severe COVID-19 treated with high-dose intravenous immunoglobulin (IVIg) at Jin Yin-tan Hospital, Wuhan, China. 

“Here we report a case series of COVID-19, all of whom were successfully treated by high-dose IVIg at the early stage of clinical deterioration,” reported Wei Cao, MD, Peking Union Medical College Hospital, Beijing, China, and colleagues. “Based on these observations, a high-dose IVIg administered at the appropriate point, could successfully block the progression of disease cascade, and finally improve the outcome of COVID-19.”

Patient 1 was aged 56 years. His symptoms began on January 19 and on January 21 was admitted after oropharyngeal swab was positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay. Both lungs were clear on CT but laboratory results reflected significant lymphocytopenia and inflammatory markers were elevated. Supportive care and empirical moxifloxacin were given. He had intermittent fever, but vital signs remained stable until January 26 when cough and shortness of breath developed. A CT scan on January 29 showed progressing infiltrations bilaterally. High-dose IVIg was started from January 28 (hospital day 7), at 25 grams per day for 5 days. Moxifloxacin was continued until February 2. On the same day following IVIg infusion, patient became afebrile. No adverse event was reported. Over the next few days, his clinical status gradually improved and supplemental oxygen was discontinued. Test results on February 5 showed recovered lymphocyte count and high-sensitive C-reactive protein (hsCRP) returned to normal range. The CT scan showed partial resolution of previous lesions. Two consecutive oropharyngeal swabs on February 2 and 3 were both negative for SARS-CoV-2 and the patient was discharged on February 5. 

Patient 2 was aged 34 years. He presented with fever and dry cough for 10 days, and was admitted on January 29, 2020. Nasopharyngeal swab was positive for SARS-CoV-2. He had a 2-year history of hypertension well controlled by valsartan and felodipine. Laboratory results on admission reflected mild thrombocytopenia and moderately elevated inflammation markers. A CT scan on January 30 indicated bilateral infiltrations and opacities, more prominent on the right side. IVIg was administered immediately (same dose as patient 1). Patient became afebrile from the second day of IVIg treatment, with a gradual improvement in breathing. A CT scan was repeated on February 3, showing prominent absorption. Nasal PCR testing turned negative for SARS-CoV-2 on February 3 and he was discharged on February 5. 

Patient 3 was aged 35 years. She was admitted on January 24, but reported malaise and low-grade fever with mild coughing since January 19. Nasopharyngeal swab was positive for SARS-CoV-2. On admission, she was afebrile and laboratory studies revealed mild lymphocytopenia and slightly elevated hsCRP. A chest CT showed multiple ground-glass opacities and infiltrations bilaterally. Oral lopinavir/ritonavir was started and continued for 2 weeks. On January 29, she developed shortness of breath, accompanied by further reduction of lymphocyte counts and elevation of hsCRP. IVIg was administered from January 29 (same dose as other patients) and methylprednisolone 40 mg/day was given for 3 days. Fever subsided after the first day of enhanced treatment. Her symptoms improved significantly 2 days later when oxygen saturation returned to 98% at ambient air. Negative PCR testing for SARS-CoV-2 were confirmed on February 2 and 3. The chest CT scan revealed radiographic resolution and she was discharged on February 9. 

“All patients were clinically improved shortly following the administration, with the temperature back to normal in 1 to 2 days, and breathing difficulties alleviating in 3 to 5 days,” the authors concluded. “Confounding factors did exist, including the use of different antivirals in 2 of the 3 patients at various time points, and short course of steroids in patient 3. Moreover, in patient 2, valsartan had been used for treating hypertension. Nevertheless, from the timeline and patterns of disease course in these 3 patients, it was most probable that high-dose IVIg was playing the leading role in their recovery.”

“Our report is limited by the small numbers of patients we included, and more evidence is needed to confirm the conclusion,” the authors added. “However, it provided an important therapeutic clue under current situation of rapid disease spreading. The timing of IVIg administration is very critical in practice. Patients might not receive much benefit when overall systemic damage has already taken place. Currently, a randomised controlled trial evaluating the efficiency of high-dose IVIg therapy in severe COVID-19 has been initiated (NCT 04261426), which would bring more evidence for IVIg using in treating such patients.”

In another case series, published in The New England Journal of Medicine, Pavan K. Bhatraju, MD, University of Washington-Harborview Medical Center, Seattle, Washington, and colleagues reported a very high mortality rate among critically ill patients with COVID-19 admitted to the intensive care units (ICUs) at 9 Seattle-area hospitals between February 24 and March 9, 2020.

“This multicenter case series describes 24 critically ill patients who presented with acute hypoxemic respiratory failure and laboratory-confirmed COVID-19 infection,” the authors wrote. “The case fatality rate of 50% in this series (to date) is similar to that reported among critically ill patients in Chinese hospitals but lower than that in a single-center experience reported from our area. Although the case fatality rate was higher in persons aged 65 years or older, it was still substantial (37%) in persons younger than 65 years. Our case fatality rate may be an underestimate, given that 3 patients remained intubated at the time data were censored.”

The 24 patients in the case series had symptoms 7±4 days before admission. The most common symptoms were cough and shortness of breath and 50% of patients had fever on admission. All patients were admitted for hypoxemic respiratory failure and 75% (18 patients) needed mechanical ventilation. Most (n = 17) of the patients also had hypotension and needed vasopressors. The majority of patients had chronic illnesses before their admission to the ICU, most commonly diabetes and chronic kidney disease and lymphocytopenia was common on hospital admission. Regarding antiviral interventions, 7 patients received compassionate-use remdesivir, but there is insufficient information to report associated outcomes. Bronchoscopy was performed in a minority of patients and did not appear to change clinical management.

No patient tested positive for influenza A, influenza B, or other respiratory viruses. Half (n = 12) the patients died between ICU day 1 and day 18, including 4 patients who had a do-not-resuscitate order on admission. Of the 12 surviving patients, 5 were discharged home, 4 were discharged from the ICU but remained in the hospital, and 3 continued to receive mechanical ventilation in the ICU.

“Our study has several notable limitations,” the authors wrote. “First, some cases had incomplete documentation of clinical symptoms, missing laboratory testing, or both. However, given the need to provide objective data and the urgent timeline, we did not approach patients to obtain additional history or biologic samples for laboratory measurement. Second, 7 (29%) patients remained in hospitals at the time of data censoring on March 23, 2020. As a result, outcomes for those patients were not known. Third, because of our focus on the critical care needs of patients with the greatest severity of illness, our sample size is small. Finally, it is possible that critically ill patients with established goals of care that were not consistent with admission to an ICU were not included in this report. Specifically, this includes patients who received care on the general medical ward that focused on comfort measures only.”

SOURCE: Open Forum Infectious Diseases, The New England Journal of Medicine
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