Successful intravenous immunoglobulin treatment in severe COVID-19 pneumonia.

We describe a 42-year old woman, admitted to our Department after 15 days of persistence of respiratory failure and treated with infusion of intravenous immunoglobulin with a successful outcome.

Introduction

Since December 2019, an illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wich emerged in Wuhan, Hubei, China, and subsequently, has caused a global pandemic of coronavirus disease 2019 (COVID-19) [1]. COVID-19 patients often develop mild symptoms such as fever, cough, muscle pain and fatigue with usually good prognosis. However, some of those infected, especially among older men with underlying diseases can developed severe life-threatening complications [2]. The World Health Organization has announced that the risk assessment of the COVID-19 is very high at the global level. Currently there is no specific vaccine or drugs for human coronavirus. Several potential therapies, including supportive interventions, immunomodulatory agents, antiviral therapy and transfusion of convalescent plasma, have been provisionally applied in clinical settings [3]. Some of these therapies have provided some benefits in the treatment of patients with COVID-19 infection. Most effective measures remain early detection and quarantine of new sources of infection, as well as early detection and support treatments for confirmed patients. Given the absence of specific antiviral therapy for SARS-CoV-2, in addition of conventional treatment some options are under investigation. Intravenous immunoglobulin (IVIG) has been clinically used as an adjunct in the treatment of severe COVID-19 pneumonia [4,5], but there are disputes on its therapeutic effect.

Yun Xie et al reported intravenous administration of small doses of glucocorticoids (1–2 mg / kg) for 5–7 days on patients in critical conditions and early administration (48 h after admission in intensive care unit) of intravenous immunoglobulin (IVIG) treatment, as adjuvant treatment of COVID-19 pneumonia. They reported a reduction of use of mechanical ventilation, hospitalization with an improvement to achieve significant clinical effectiveness [4]. We here described a 42-years old woman, admitted to our Department after 15 days of persistence of respiratory failure and treated with infusion of intravenous immunoglobulin.

Case report

A healthy 42-year-old Caucasian woman with controlled hypothyroidism developed fever, loss of appetitie, diarrheam fatigue, cough and anosmia over about 7 days. She was admitted in Emergency Department on April 9, 2020. Physical examination showed fever (38 °C) and her pulse oxygen saturation was 90% in ambient air. The patient's BMI was 24, with a normal weight. Subsequently, at that time, her oxygen saturation was 95% on 2 L/min oxygen flow via nasal cannula with a respiratory rate of 24 times per minute. Laboratory examination revealed mild leukocytosis (14.980/mmc) with lymphopenia (600/uL), elevated C-reactive protein (CRP) and lactate dehydrogenase (LDH) (6.7 mg/dL, 564 IU/L, respectively). Levels of interleukin-6 (IL-6) were slightly higher 15.7 pg/mL Routine chemistry showed high levels of transaminases (AST 47 and ALT 87 U/L) and electrolyte, and blood coagulation tests showed no abnormalities. Bacterial cultures and the PCR for other respiratory viruses were negative. Infection from SARS-CoV-2 was confirmed on swab test in real time polymerase chain reaction assay. On hospital ward the patient was treated with 400 mg of hydroxychloroquine once daily (the QTc interval was monitored daily) plus azithromycin 500 mg once daily. The computed tomography (CT) scan performed on April 11 showed large consolidations and bilateral ground glass opacities (GGO) areas such as progressive Covid-19 pneumonia (Fig. 1). After 6 days oxygen demand increased with a worsening of clinical conditions and for this reason she was transferred at the Sub Intensive Respiratory Department. She had no subjective dyspnea under reservoir mask (FiO2 60%), with respiratory rate over 30 times per minute. The CT scan performed on April 16 showed rapidly percentage increase of bilateral infiltrations and consolidations (Fig. 2). Laboratory examination showed white blood cell (WBC) count at 11.5600/mmc, with lymphopenia 500/uL of CRP and LDH elevated up to 8,7 mg/dL and 845 IU/L. Routine chemistry, electrolyte, and blood coagulation tests again revealed no abnormalities except mildly elevated AST and ALT (149 U/L and 170 U/L). The level of IL-6 was 18 pg/mL. Screening tests were negative for multiple respiratory pathogens. Arterial blood gases (ABG) showed: pH 7.42, PaCO2 42 mmHg, PaO2 116 mmHg, HCO3 27.2 mmol/L with reservoir mask (FiO2 66%) with PaO2/FIO2 ratio of 181 mmHg. Respiratory rate was 32 times per minute. We decided to start treatment with Continuous Positive Airway Pressure (CPAP). Initial HACOR SCORE was 4. We set up support pressure of CPAP in 7 cmH2O and FiO2 30%, whit oro/nasal interface and double branch. After 1 h there was an improvement in arterial blood gases: pH 7.42, PaCO2 41 mmHg, PaO2 85 mmHg, HCO3− 26.6 mmol/L with PaO2/FiO2 ratio of 283 mmHg, and HACOR SCORE was 0. Respiratory rate of 18 times per minute. After obtaining informed consent from the patient, treatment with IVIG has been started. Recent data from the literature have reported improvements with significant clinical efficacy with use intravenous immunoglobulin. Furthermore, this choice was made to avoid use of steroids which determine a reduction of viral clearence. IVIG was begun, specifically 450 mL (5 mL/kg) at 36 mL/h x 3 days with premedication with antihistamine and rehydration. Mild hypotension observed during routine check precipitated a decrease in infusion to 28 mL/h and subsequently extended total administration to 4 days. At the end of the administration with IVIG the respiratory function of the patient is significantly improved by rise of arterial blood gas values (ABG showed pH 7.40, PaCO2 45 mmHg, PaO2 103 mmHg, HCO3 27.9 mmol/L with PaO2/FIO2 ratio 412). This led to the stop of respiratory support. The improvement in clinical and pulmonary function remained constant in the days to follow the infusion. Patient at sixth day after IVIG showed on ABG in current air: pH 7.38, PaCO2 36 mmHg, PaO2 90 mmHg, HCO3 25 mmol/L with PaO2/FIO2 433 mmHg. On April 24, a further chest CT scan was performed and showed a massive reduction in parenchymal consolidations, residual at present widespread areas of GGO parenchymal hyperattenuation and consolidating streaks with greater left lower lobar expression (Fig. 3).

Fig. 1

Parenchymal opacity of the GGO type and consolidations, patchy, with distribution predominantly declive and longitudinal gradient.

Fig. 2

Unchanged presence of multiple consolidation patches known, associated with diffuse parenchymal attenuation of the GGO, and extended with greater involvement of the lung.

Fig. 3

Significant reduction in both sides of the multiple consolidative patches with few diffuse GGO areas and consolidations.

Discussion

The COVID-19 outbreak is an unprecedent crisis for public health and the global economy and has had a huge impact on the world. Scientists around the world are evaluating COVID-19 effective treatments. Several potential therapies, including supportive interventions, immunomodulatory agents, antiviral therapy and transfusion of convalescent plasma, have been provisionally applied in clinical settings. Current guidelines recommend that systemic corticosteroids should not be routinely administered for the treatment of COVID-19 due to the lack of evidence of its clinical efficacy on reducing mortality [5]. The recent article on the risk factors associated with ARDS and death among COVID-19 patients showed that treatment with methylprednisolone may be helpful in reducing the risk of death for patients who develop ARDS [6]. However, it is believed that corticosteroids could inhibit the appropriate immune responses and viral clearance and delay the production of antibodies [6].

IVIG could be applied as adjuvant treatment of patients in critical condition. Being a blood product purified from the mixed plasma of healthy people, the protein is the main component and is rich in bacterial and viral IgG antibodies [10]. Continuous infusion may improve the level of IgG in serum, effectively neutralizing pathogens in the respiratory tract of the patient's system, thereby promoting recovery from illness and shortening the course of the disease. IVIG also can improve the body's defense, block the receptors associated with the target cell and prevent the pathogen to further damage the target cell [7]. IVIG acting as an agent that modifies the body's immune response as it does on vasculitis, ITP and AIHA and Kawasaki. In addition, the use of IVIG can also influence the process of differentiation and maturation of lymphocytes, hinder the normal immune response of white blood cells, inhibit the production of inflammatory factors and thus reduce the inflammatory lesion encountered by patients [[8], [9], [10]]. IVIG acting as an agent that modifies the body's immune response as it does on vasculitis, ITP and AIHA and Kawasaki. A previous meta-analysis of IVIG in SARS infection concluded that it was not clear whether the IVIG improved the prognosis [11]. There are also reports of the literature on the use of IVIG in infection by MERS, but there is no evidence that IVIG has anti-MERS activity, since the specific efficacy has not been reported [9]. Studies on infection with influenza viruses such as H1N1, have shown that IVIG may prevent a serious infection with pandemic influenza. A multicenter, double-blind, randomized, controlled hyperimmune globulin used to treat patients with severe H1N1 infection in 2009 found that the use of h-IVIG in the treatment of severe H1N1 within 5 days from onset of symptoms was associated with reduction in viral load and reduction in mortality [9].

It is therefore worth considering when to use IVIG to help treat COVID-19. The IVIG has been clinically used as an adjunct in the treatment of severe pneumonia caused by influenza, but there are disputes on its therapeutic effect on COVID-19 pneumonia, despite the inclusion in the seventh edition of the guidelines stating that can be considered for use in critically ill and critically ill patients [9]. In our case the clinical intravenous administration of immunoglobulins has allowed a rapid clinical improvement demonstrated by the short period of need for respiratory support with CPAP, by the improvement of the blood values and gas and the radiological findings.

The patient was discharged after 15 days from the last CT with two negative swabs and reducing inflammatory markers, normalization of liver function and recovery of lung function (Table 1)

Table 1

Clinical and laboratory data of the trend of the patient during hospitalization.

Support	Ambient Air							Ambient Air
				C-PAP
							Venturi Mask
Antimicrobial
Therapy	Azithromycin
	Hydroxychloroquine
				IVIG
Days		11.04	14.04	16.04	17.04	18.04	19.04	20.04	21.04	23.04
	Temperature, °C	37,5	36,7	36,4	36,2	36,3	36,4	36	36	35,6
	wbc, 10³/l	3,05	5,34	4,21	5,61	8,84	4,99	5,71	5,44	6,79
	CrP, mg/dl	8,3	4,7	2,2	1,1	0,5	0,4	0,4	0,4	0,4
	D-dimer, ng/mL	151	178	343	170	165	200	363	300	265
	AST, U/L	31	44	114	149	77	38	25	30	23
	ALT, U/L	46	55	116	187	152	100	80	76	65
	GGT, U/L	15	17	21	27	35	30	26	22	20
	Lymphocytes %	17,7	14	21,4	11,1	7,1	13,2	18,4	17,8	17,1
	Platelets	153	258	270	262	304	243	268	273	264
	Creatinin, mg/dL	0,5	0,6	0,4	0,4	0,5	0,4	0,5	0,4	0,5
	pO2, mmHg	56	51	91	109	103	90	89	91	88
	P/F ratio	181	242	303	363	412	375	424	433	419
	Lactate	0,9	1,9	0,8	0,6	1,2	1,1	2	2	3
	Ves	42	50	52	49	38	49	43	34	30

Conclusion

In summary the early use, in selected patients, of IVIG, as an adjuvant treatment for COVID-19 pneumonia, can reduce the use of mechanical ventilation, hospitalization and promote early recovery of patients with an improvement to achieve significant clinical effectiveness.

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