Patient cohort, demographics, and baseline clinical features
Fifty-five cases were identified: 10 (18.2%) required hospitalization and 45 (81.8%) received ambulatory care. Demographics and baseline clinical features are outlined in Table
1. Age was similar between groups. The racial and ethnic distribution differed between groups: a higher proportion of African American patients were encountered in the hospitalized group (OR 7.78, 95% CI [1.46–55.38];
p = 0.006), while Caucasian patients predominated in the ambulatory group (OR 0.14, 95% CI [0.01–0.83];
p = 0.01).
Table 1
Demographic and baseline clinical features of children with rheumatic diseases and COVID-19
Demographics |
Age in years | 16 | (14–18) | 17 | (16–19) | 16 | (13–17) | | 0.07 |
Female | 43 | (78.2) | 7 | (70.0) | 36 | (80.0) | 0.59 (0.11–4.22) | 0.67 |
African American | 17 | (30.9) | 7 | (70.0) | 10 | (22.2) | 7.78 (1.46–55.38) | 0.006 |
Asian | 1 | (1.8) | 0 | (0) | 1 | (2.2) | 0 (0–175.02) | 1 |
Caucasian | 31 | (56.4) | 2 | (20.0) | 29 | (64.4) | 0.14 (0.01–0.83) | 0.01 |
Hispanic or Latino | 6 | (10.9) | 1 | (10.0) | 5 | (11.1) | 0.89 (0.02–9.54) | 1 |
Baseline clinical features |
Comorbidities | 27 | (49.1) | 6 | (60.0) | 21 | (46.7) | 1.69 (0.35–9.35) | 0.50 |
Primary rheumatic disease |
Juvenile Idiopathic arthritis | 17 | (30.9) | 1 | (10.0) | 16 | (35.6) | 0.21 (0.004–1.73) | 0.15 |
Systemic lupus erythematosus | 14 | (25.5) | 5 | (50.0) | 9 | (20.0) | 3.88 (0.72–21.23) | 0.1 |
Juvenile Dermatomyositis | 6 | (10.9) | 0 | (0) | 6 | (13.3) | 0 (0–3.94) | 0.58 |
Other | 18 | (32.7) | 4 | (40.0) | 14 | (31.1) | 1.46 (0.26–7.38) | 0.71 |
Active rheumatic disease | 28 | (50.9) | 9 | (90.0) | 19 | (42.2) | 11.83 (1.43–558.37) | 0.01 |
Immunomodulatory medications |
Oral corticosteroids < 10 mg | 8 | (14.5) | 3 | (30.0) | 5 | (11.1) | 3.33 (0.42–22.33) | 0.15 |
Oral corticosteroids ≥10 mg | 10 | (18.2) | 6 | (60.0) | 4 | (8.9) | 14.12 (2.31–106.04) | 0.001 |
IV pulse corticosteroids | 3 | (5.5) | 0 | (0.0) | 3 | (6.7) | 0 (0–11.40) | 1 |
Hydroxychloroquine | 27 | (49.1) | 7 | (70.0) | 20 | (44.4) | 2.89 (0.56–19.35) | 0.18 |
Other cDMARDsa | 20 | (36.4) | 2 | (20.0) | 18 | (40.0) | 0.38 (0.03–2.22) | 0.3 |
Mycophenolate | 16 | (29.1) | 7 | (70.0) | 9 | (20.0) | 8.84 (1.64–63.88) | 0.004 |
Tofacitinib | 2 | (3.6) | 1 | (10.0) | 1 | (2.2) | 4.69 (0.06–390.81) | 0.33 |
Intravenous immunoglobulin | 4 | (7.3) | 0 | (0.0) | 4 | (8.9) | 0 (0–7.15) | 1 |
Cyclophosphamide | 4 | (7.3) | 1 | (10.0) | 3 | (6.7) | 1.54 (0.03–21.94) | 0.56 |
TNFi | 14 | (25.5) | 0 | (0.0) | 14 | (31.1) | 0 (0–1.17) | 0.05 |
Rituximab | 7 | (12.7) | 5 | (50.0) | 2 | (2.2) | 19.40 (2.45–254.14) | 0.001 |
Other bDMARDsb | 8 | (14.5) | 2 | (20.0) | 6 | (13.3) | 0.73 (0.01–7.29) | 1 |
None | 3 | (5.5) | 0 | (0.0) | 3 | (6.7) | 0 (0–11.40) | 1 |
Severe Immunosupressionc | 17 | (32.7) | 9 | (90.0) | 8 | (19.0) | 34.80 (3.94–1704.26) | < 0.001 |
The frequency of underlying comorbidities was comparable between groups. Reported comorbidities consisted of: asthma (n = 10), hypertension (n = 7), obesity (n = 5), inflammatory bowel disease (n = 4), anemia of chronic disease (n = 2), immunoglobulin G deficiency (n = 2), hypothyroidism (n = 2), end-stage renal disease on chronic dialysis (n = 2), and one patient each had pulmonary hypertension, chronic kidney disease, post-renal transplant status, left ventricular hypertrophy, chronic diarrhea, cholestasis, adrenal insufficiency, hyperparathyroidism, thyroid disease, chronic neutropenia, sickle cell disease, recurrent infections, chronic deep venous thrombosis, and Wilms tumor. No smoking or diabetes were identified in either group. Patients with cardiovascular disease, namely left ventricular hypertrophy and hypertension, were more likely to be in the hospitalized group (OR 19.40, 95% CI [2.45–254.14]; p = 0.001). No significant differences were observed regarding the presence of the remaining specific comorbidities between groups.
Juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), and juvenile dermatomyositis (JDM) were the most common primary rheumatic diagnoses among children with COVID-19 (Table
1). Undifferentiated connective tissue disease (
n = 3), idiopathic uveitis (n = 3), Behcet’s disease (n = 3), overlap syndrome (
n = 2), sarcoidosis (n = 2), rheumatoid arthritis (n = 2), systemic scleroderma (
n = 1), Takayasu’s arteritis (n = 1), and Anti-neutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (n = 1) were also identified as primary rheumatic diagnoses. Five patients had an additional rheumatic comorbidity: SLE+ history of macrophage activation syndrome (n = 2), SLE+ rheumatoid arthritis (n = 1), JIA+ Sjogren’s syndrome (n = 1), ANCA-associated vasculitis+ anti-glomerular basement membrane disease. Active disease was more commonly encountered in the hospitalized group (OR 11.83, 95% CI [1.43–558.37];
p = 0.01).
The majority of patients in both groups were taking at least one immunomodulatory medication, as detailed in Table
1. Besides those, additional immunosuppressants used in the ambulatory group included apremilast (
n = 1), azathioprine (n = 1), cyclosporine (n = 1), tacrolimus (n = 1), and colchicine (n = 1). NSAID use was observed in 5 (50%) patients in the hospitalized group and 21 (46.7%) patients in the ambulatory group (
p = 1). The use of medium/high-dose CS (OR 14.12; 95% CI [2.31–106.04];
p = 0.001), mycophenolate (OR 8.84; 95% CI [1.64–63.88];
p = 0.004) and rituximab (OR 19.40; 95% CI [2.45–254.14]; p = 0.001) increased the odds of hospitalization. Patients using tumor necrosis factor-alpha inhibitors (TNFi) had decreased odds of admission (OR 0; 95% CI [0–1.17];
p = 0.05). No patients receiving intravenous immunoglobulin (IVIG) or IV pulse CS were hospitalized. No significant differences regarding use of other DMARDs were observed. Severely immunosuppressed individuals had increased odds of hospitalization (OR 34.80; 95% CI [3.94–1704.26];
p < 0.001).
COVID-19 exposure, symptoms and diagnosis
Exposure to a close contact with confirmed COVID-19 was reported by 5 (50%) patients in the hospitalized group versus 26 (57.8%) patients in the ambulatory group (p = 0.75).
Table
2 lists patient reported symptoms for both groups. Patients with fever, dyspnea, chest pain, rash and myalgias had increased odds of hospitalization (
p < 0.05 for each comparison).
Table 2
Clinical presentation of COVID-19 in children with rheumatic diseases
Fever | 17 | (30.9) | 7 | (70.0) | 10 | (22.2) | 7.78 (1.46–55.38) | 0.006 |
Rhinorrhea/Congestion | 13 | (23.6) | 2 | (20.0) | 11 | (24.4) | 0.78 (0.07–4.79) | 1 |
Cough | 20 | (36.4) | 4 | (40.0) | 16 | (35.6) | 1.20 (0.22–5.99) | 1 |
Dyspnea | 5 | (9.1) | 4 | (40.0) | 1 | (2.2) | 26.28 (2.17–1459.25) | 0.003 |
Chest pain | 6 | (6) | 4 | (40.0) | 2 | (4.4) | 13.20 (1.53–175.79) | 0.007 |
Myalgias | 12 | (21.8) | 5 | (50.0) | 7 | (15.6) | 5.21 (0.94–30.12) | 0.03 |
Abdominal pain | 4 | (7.3) | 2 | (20.0) | 2 | (4.4) | 5.14 (0.32–80.65) | 0.15 |
Anorexia/Nausea/Emesis | 8 | (14.5) | 3 | (30.0) | 5 | (11.1) | 3.33 (0.42–22.34) | 0.15 |
Diarrhea | 10 | (18.2) | 4 | (40.0) | 6 | (13.3) | 4.18 (0.67–24.99) | 0.07 |
Anosmia/Ageusia | 14 | (25.5) | 2 | (20.0) | 12 | (26.7) | 0.69 (0.06–4.21) | 1 |
Rash | 5 | (9.1) | 4 | (40.0) | 1 | (2.2) | 26.28 (2.17–1459.25) | 0.003 |
Fatigue/Malaise | 16 | (29.1) | 2 | (20.0) | 14 | (31.1) | 0.56 (0.05–3.34) | 0.7 |
Sore throat | 12 | (21.8) | 2 | (20.0) | 10 | (22.2) | 0.88 (0.08–5.50) | 1 |
Headache | 12 | (21.8) | 2 | (20.0) | 10 | (22.2) | 0.88 (0.08–5.50) | 1 |
Asymptomatic | 10 | (18.2) | 0 | (0.0) | 10 | (22.2) | 0 (0–1.92) | 0.18 |
Ten patients (18.2%) were asymptomatic, all in the ambulatory group. Of those, one patient had a lung infiltrate in a surveillance chest tomography for metastatic Wilms tumor, prompting SARS-CoV-2 testing. The remaining 9 patients were tested due to exposure to a close contact with confirmed COVID-19 or during routine screening at their educational institution.
Fifteen patients had confirmatory PCR testing performed at CHOA; the rest were diagnosed at an outside facility. Of the 10 hospitalized patients, three were known to be SARS-CoV-2 positive prior to admission: patients 1 and 9 were tested one week earlier, with subsequent worsening clinical status requiring hospitalization; for patient 3, PCR test results became available while still in the emergency room.
COVID-19 diagnosis was reported to Rheumatology during the acute infection period in 28 (62.2%) ambulatory and 9 (90%) hospitalized patients; the report was delayed by up 3 months for 17 (37.8%) ambulatory patients, and by 6 weeks for 1 (10%) patient admitted to an outside hospital.
Complications, management and outcomes
Immunomodulatory management during the acute COVID-19 period did not differ between groups: medications were temporarily discontinued in 5 (50%) hospitalized patients and 16 (38.1%) ambulatory patients on immunosuppression (p = 0.50).
Rheumatic disease flares were observed in 6 hospitalized patients versus 1 (2.2%) ambulatory patient (OR 55.95; 95% CI [5.16–3023.74]; p < 0.001). Disease flare was preceded by medication discontinuation in two patients (7 and 33). Patient 33 experienced gastrointestinal symptoms (without fever or other organ involvement) from Behcet’s disease after holding adalimumab for 2 weeks; this was successfully managed by restarting the medication. Patient 7 developed flare symptoms after running out of anakinra; this improved after anakinra re-introduction and increased CS doses.
In the ambulatory group, COVID-19 treatment was largely symptomatic. Inpatient care, complications and outcomes of hospitalized patients are detailed in Table
3. Four patients required Intensive Care Unit (ICU) admission. One patient died, after having required mechanical ventilation and extracorporeal membrane oxygenation. The possibility of multisystem inflammatory syndrome in children (MIS-C) was considered but ultimately ruled out in patients 7, 9 and 10 (Table
3), based on lack of cardiac involvement, gastrointestinal symptoms explained by the presence of co-infection, and overall evolution of symptoms. No confirmed MIS-C cases were identified in this cohort. No additional late complications were encountered after a median post-COVID-19 follow-up period of 48 days.
Table 3
Clinical features and hospital course of children with rheumatic diseases hospitalized with COVID-19
1 | 16/F | SLE (with ILD) | N | | HCQ, PDN 2.5 mg daily, MMF, RTX | Continued | Fever, cough, dyspnea | 0 | 2 | 1 | N | N | N | Y | N | None | | Pneumonia | Survived |
2 | 19/F | SLE (with LN) | Y | HTN | HCQ, PDN 40 mg daily | Continued | Fever, cough, dyspnea, anosmia/ageusia | 1 | 5 | 2 | N | N | LFNC | Y | Y | Before | IVMP | Pneumonia, AKI | Survived |
3 | 17/F | Overlap sd. (with ILD) | Y | | HCQ, PDN 30 mg daily, MMF, IV CYC | MMF and HCQ held | Fever, sore throat, dyspnea, myalgia, diarrhea, vomiting | 4 | 8 | 1 | Y | Y | HFNC | Y | Y | Before | Increased PDN dose | | Survived |
4 | 19/F | SLE+ RA | Y | | HCQ, PDN 10 mg daily, MTX, MMF, RTX | Continued | Myalgia, chest pain | 0 | 4 | 1 | N | N | N | N | N | Before | IVMP, increased PDN dose | | Survived |
5 | 19/F | JIA | Y | | Tofacitinib | Continued | Fever, abdominal pain | 0 | 2 | 1 | N | N | N | Y | N | None | | Urosepsis | Survived |
6 | 19/F | SLE (with LN) | Y | Hyperparathyroidism, LVH, HTN, anemia of chronic disease, s/p renal transplant | HCQ, PDN 5 mg daily, tacrolimus, MMF, RTX | MMF held | Fever, cough, diarrhea, anosmia/ageusia, rhinorrhea, fatigue, chest pain, rash | 4 | 17 | 1 | N | Y | HFNC | Y | Y | Concurrent | IVMP, increased PDN dose, IV CYC | Renal failure requiring HD, pneumonia | Survived |
7 | 17/M | SLE+ MAS | Y | HTN | HCQ, PDN 20 mg daily, MMF, ANK | ANK heldd | Fever, myalgias, headaches, vomiting, diarrhea, rash f | 0 | 4 | 1 | N | N | N | Y | N | After | IVMP, increased PDN dose | C. difficile colitis | Survived |
8 | 16/M | Sarcoidosis (with ILD) | Y | SCD, Cholestasis, pulmonary HTN | PDN 30 mg daily, MMF | MMF held | Myalgia | 0 | 5 | 1 | Y | N | LFNC | N | Y | None | | | Survived |
9 | 14/M | Overlap sd. (with LN) | Y | Asthma, HTN | HCQ, PDN 60 mg daily, MMF RTX | Continued | Rash, chest pain | 0 | 3 | 1 | N | N | N | N | Y | None | | Conjunctivitis 3 weeks post-admissione | Survived |
10 | 14/F | AAV+ anti-GBM disease (with RLD) | Y | ESRD on PD, HTN, acquired IgG deficiency | PDN 5 mg daily, leflunomide, RTX | Leflunomide held | Fever, fatigue, sore throat, nausea/vomiting, diarrhea, abdominal pain, dyspnea, chest pain, rash, myalgias f | 26 | 41 | 3 | N | N | MV/ ECMO | Y | N | After | PLEX, IVMP, IVIG, IV CYC, RTX | Pneumonia, C. difficile colitis, cytokine storm requiring ANK and TCZ | Deceased |