Clinical Observation of COVID-19 in a Patient With an Acquired Humoral Deficiency Secondary to Chemotherapeutic Agents

Introduction

The coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created a multifaceted global devastation. ¹ There is an existing need for information on the clinical course of COVID-19 in patients with immunodeficiency. We describe the course of a patient with COVID-19 in the setting of an acquired humoral deficiency as a result of chemotherapeutic treatment for rheumatologic conditions.

Case Report

A 49-year-old Caucasian male presented with a two-week history of sinusitis, nonproductive cough, and sore throat, which progressed to a fever up to 38.9 °C unrelieved by acetaminophen. The patient also experienced generalized myalgia, and had a two-day history of decreased appetite, diarrhea and frontal headache. He tested positive for SARS-CoV-2 by polymerase chain reaction (PCR) assay and was quarantined and medically managed at home for seven days prior to hospital admission. He was admitted due to hypoxemia with oxygen saturation in the low 80 s.

The patient’s past medical history was significant for mixed connective tissue disease, rheumatoid arthritis, and systemic lupus erythematosus. The patients’ rheumatological symptoms were controlled by a combination of methotrexate weekly and rituximab every six months since 2008. However, the prolonged course of rituximab resulted in chronic pansinusitis which led to a diagnosis of acquired humoral deficiency. The patient was referred by an otolaryngologist for an immunological evaluation because his chronic pansinusitis did not resolve with septoplasty and bilateral sinus surgery followed by several rounds of clarithromycin. His laboratory results revealed poor humoral function as demonstrated by peripheral lymphopenia with zero absolute CD19 count with an absence of IgA and IgM, but a normal level of IgG (Table 1). The IgG serology showed no titer response following a pneumococcal vaccination. Because rituximab was the key in management of his rheumatological conditions, intravenous immunoglobulin (IVIG) was initiated. Initially, the IVIG treatment and dosage were targeted at 400 mg/kg per dose every 4 weeks, increased to 600 mg/kg per dose every 4 weeks, then eventually to 600 mg/kg per dose every 3 weeks along with prophylactic azithromycin daily to effectively manage his chronic sinus infections. The patient’s last IVIG and last dose of rituximab was seventeen days prior to hospitalization and two days prior to the start of a non-productive cough.

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Table 1.

Humoral Panel at Diagnosis of Acquired Humoral Deficiency in 2017.

Test name	Result
IgA, serum (mg/dL)	<5 L
IgG, serum (mg/dL)	739
IgM, serum (mg/dL)	<5 L
IgG subclass 1 (mg/dL)	599
IgG subclass 2 (mg/dL)	89 L
IgG subclass 3 (mg/dL)	34
IgG subclass 4 (mg/dL)	13
CD3 absolute (×109/L)	0.706 L
CD3+CD4+ absolute (×109/L)	0.540
CD3+CD8+ absolute (×109/L)	0.174
CD19 absolute (×109/L)	0 L
CD3 %	85
CD3+CD4+ %	65 H
CD3+CD8+ %	21
CD4/CD8 ratio	3.10
CD3+CD4−CD8−%	1
CD45 %	100
CD3-CD16+CD56+ %	14
CD3-CD16+CD56+ absolute (×109/L)	0.116
CD19 %	0 L
Mannose binding lectin	967
C3 complement	140
C4 complement	21

L = low; H = high.Note. The boldface values signify abnormal laboratory values (higher or lower than normal reference range).

On admission, the patient presented with tachypnea and visible respiratory distress. His pulse oximetry was 96% on 2 L/min of oxygen via nasal cannula. The vital sign measurements were as follows: temperature of 37.6 °C, blood pressure of 119/87 mmHg, heart rate at 82 beats per minute, and respiratory rate at 20 breaths per minute. The auscultation of the lungs revealed fine bibasilar inspiratory crackles with symmetric chest expansion. The initial chest X-ray revealed cardiomediastinal silhouette enlargement with increased pulmonary vascularity and mild bibasilar atelectasis. The complete blood count demonstrated leukopenia and lymphocytopenia, which were both normal in January 2020 (Table 2). At this time, the patient was experimentally given hydroxychloroquine and azithromycin, but the lack of pulmonary infiltrate on the initial chest X-ray did not qualify him for the remdesivir trial.

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Table 2.

Laboratory Results Prior and During COVID-19.

Timeline	3 months prior to COVID-19	At hospital admission	In ICU	At discharge
WBC (cells/L)	4.5 × 109	3.2 × 109 L	3.2 × 109 L	4.1 × 109 L
Absolute lymphocytes (cells/µL)	1157	510 L	330 L	1550
C-reactive protein (mg/L)	2.5 H	5.5 H	10.83 H	3.34 H
Aspartate transaminase, serum (U/L)	27	33	122 H	49 H
Alanine aminotransferase, serum (U/L)	37	25	89 H	70 H
PT (sec)			1.3 H	1.2 H
PTT (sec)			14.6 H	12.9 H
APTT (sec)			23 L	32
D-dimer (ng/mL)		403	887 H	433
Fibrinogen (mg/dL)			673 H
Troponin I (ng/mL)		<0.02	0.04 H	<0.02
Ferritin, sesum (ng/mL)		110	685 H
Glucose, serum (mg/dL)		135 H	75	87
Ca (mg/dL)		8.4 L	7.7 L	8.7
Na (mmol/L)		137	131 L	141
Cl (mmol/L)		101	94 L	103
BUN (mg/dL)		11	31 H	7
Creatinine (mg/dL)		0.79	0.9	0.51
Albumin (g/dL)		3.6	2.4 L	3 L
Lactate dehydrogenase (U/L)		244	592 H	257 H
pH, arterial			7.53 H
pCO2, arterial			35 L
pO2, arterial			53 L
Bicarbonate, arterial (mmol/L)		30	26	30
Anion gap (mEq/L)		14	9 L	13
IL-6 (pg/mL)			22 H
IgA, serum (mg/dL)	<5 L		<5 L
IgG, serum (mg/dL)	1234		1100
IgM, serum (mg/dL)	<5 L		<5 L

L = low; H = high.Note. The boldface values signify abnormal laboratory values (higher or lower than normal reference range).

On hospital day four, the patient was transferred to the intensive care unit due to worsening hypoxemia. The laboratory results in Table 2 demonstrated persistent leukopenia and lymphocytopenia with a new elevation of IL-6, C reactive protein, D-dimer, ferritin, glucose, alanine aminotransferase, aspartate transaminase, and lactate dehydrogenase levels. On day five, IVIG was given at 600 mg/kg followed by another 600 mg/kg dose two weeks later. Supplemental oxygen via high flow nasal cannula was initiated at 15 L/min and titrated up to 20 L/min by day twelve. A repeat chest X-ray revealed multifocal ground-glass consolidative opacity that was more significant in the left lower lung with worse aeration compared to prior study.

His respiratory condition was complicated by abdominal distention with diarrhea and ileus, necessitating a nasogastric tube placement. An abdominal computed tomography study was completed on day twenty-six revealing thickening of the colon. On day twenty-seven, he was discharged from the intensive care unit. Cultures of Histoplasma, Pneumocystic jiroveci, Staphylococcus aureus, Rhinovirus, Metapneumovirus, Adenovirus, and Clostridium difficile were found negative for respiratory and gastrointestinal symptoms; however, SARS-CoV-2 remained positive via PCR assay. A computed tomography of the chest was performed on day thirty-three showing diffuse patchy infiltrates in both lungs, worse in the right upper and middle lobes as shown in Figure 1. The patient was discharged to home after forty-one days of hospitalization with oxygen supplementation only with ambulation and a complete resolution of diarrhea despite still being tested positive for SARS-CoV-2. The patient eventually was cleared of SARS-CoV-2 after three different PCR assays at three weeks post hospital discharge.

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Figure 1.

Clinical timeline of COVID-19 and a computed tomography showing diffuse patchy infiltrates in both lungs, worse in the right upper and middle lobes.

Discussion

Individuals diagnosed with primary or acquired immunodeficiencies are at high risk for fatal outcomes with COVID-19. ² , ³ Guan et al. found that the mean hospitalization stay for an immunocompetent patient was 12.8 days compared to the forty-two-day length of stay for our patient. ⁴ COVID-19 pneumonia was described in previously reported cases with primary immunodeficient diseases showing similar respiratory decline but followed a shorter course of hospitalization (14–25 days) when compared to our patient’s length of stay.^5–7 According to current data, patients with immunodeficiency have longer lengths of hospitalization compared to immunocompetent individuals.

The “cytokine release syndrome” has been shown to be associate with severe COVID-19 conditions. In the setting of lymphocytopenia observed in severe COVID-19, the cytokine storm release has been suggested to be facilitated by leukocytes other than T lymphocytes. ⁸ The possible role of B lymphocytes in the cytokine storm in COVID-19 was discussed by Quinti et al., evidenced by a milder presentation of COVID-19 in patients with agammaglobulinemia when compared to a more severe course in patients with common variable immunodeficiency. ⁵ Similar observations were reported for two patients with X-linked agammaglobulinemia in Italy infected with SARS-CoV-2 who were able to recover without requiring intensive level of care. ⁶ Our patient demonstrated a form of immunodeficiency as the result of a chemotherapeutic agent, and his clinical course appeared to be more severe.

Rituximab is known to modulate autoimmune responses by suppressing the humoral function and decreasing the body’s ability to respond to infection independent of COVID-19. ⁹ In our case, while providing an essential role in managing the rheumatologic conditions, rituximab resulted in an acquired humoral deficiency requiring IVIG to relieve chronic sinus infections prior to COVID-19. The continuation of IVIG regimen during the course of COVID-19 conferred the importance of passive immunity in helping our patient to recover from COVID-19 pneumonia without the presence of superimposed infections. The highlighted role of IVIG in immunocompromised patients ⁶ , ⁷ further supported the exploration of the effectiveness of convalescent plasma therapy for COVID-19. Anti-IL-6 monoclonal antibodies were experimentally given to primary immunodeficient patients in Italy to manage the cytokine storm, ⁵ but they are currently under phase 2 clinical trials for immunocompetent patients with COVID-19 (Clinicaltrials.gov identifier: NCT04322773).¹⁰

The inflammatory response to SARS-CoV-2 may be milder in patients with agammaglobulinemia due to the lack of immunoglobulin mediated inflammatory process. It is possible that the pathway which SARS-CoV-2 amplifies inflammatory response is either absent or diminished in patients with agammaglobulinemia, which results in milder course of COVID-19. On the other hand, CVID or acquired humoral deficiencies may have some intact inflammatory mediated pathways that allow SARS-CoV-2 to induce the cytokine storm, which results in a worse clinical presentation of COVID-19. More studies are necessary to shed light on the immunological response to SARS-CoV-2 and its impact on immunocompromised and immunocompetent individuals. We describe the course of a patient with COVID-19 in the setting of an acquired humoral deficiency as a result of chemotherapeutic treatment for rheumatologic conditions.