Multisystem inflammatory syndrome identified in adults

Boudhabhay et al., 2020^{Footnote 6}
France
16 September 2020
The patient was a 46-year-old male of African descent with a history of hypertension and obesity

Fever and other signs and symptoms:

• Admitted for hypertensive emergency (189/123 mmHg) and fever (duration not reported)

Evidence of coagulopathy and renal involvement:

• Acute kidney injury: Serum creatinine (sCr) level was 169 µmol/L associated with 1 g/day proteinuria, aseptic pyuria, no hematuria and low natriuresis (<20 mmol/L)
• Renal biopsy light microscopy revealed typical lesions of thrombotic microangiopathy (TMA) including fibrin thrombi within glomeruli and myxoid intimal alterations of arterioles and small to medium-sized renal arteries
• On Day 4, the patient presented evanescent facial erythema and developed acute myocardial dysfunction with reduced left ventricular ejection fraction to 40%, pericardial effusion
• On Day 5, the patient presented with neurologic impairment. Abnormal supratentorial periventricular magnetic resonance imaging (MRI) signals responsible for a restriction of the diffusion due to an acute vasculitis

PCR and serology for SARS-CoV-2:

• RT-PCR negative, IgM negative and IgG positive (no previous COVID-19 symptoms were reported)

Inflammatory markers:

• CRP level was 312 mg/L
• Thrombocytopenia: neutrophil count was 18.7 × 109/L
• High sensitive troponin (hsTroponin) elevation

• No immunosuppressive treatment was introduced because of concomitant tracheal aspiration positive for Klebsiella aerogenes treated with trimethoprim sulfamethoxazole
• Dobutamine and renal replacement therapy (RRT)
• Specific complement inhibition with eculizumab therapy (900 mg)
• On Day 5 of hospitalization, neurologic impairment presented with coma leading to intubation and mechanical ventilation

The patient was discharged after 30 days in hospital

Chowdhary et al., 2021^{Footnote 7}
United Kingdom
September 2020
The patient was a 26-year-old male
Ethnicity was not reported
The presence or absence of comorbidity was not reported
Exposure to SARS-CoV-2 was reported

Fever and other signs and symptoms:

• Patient was admitted after five days of fever
• Dry cough, myalgia, diarrhea, vomiting and abdominal pain
• Patient was hypotensive and hypoxic upon admission

One or more organs involved (pulmonary, cardiac, digestive):

• CT showed bilateral pulmonary basal ground-glass changes and bowel edema
• Initial transthoracic echocardiography demonstrated severe left ventricular systolic dysfunction with pericardial effusion
• CT of the abdomen demonstrating mesenteric lymphadenopathy and small bowel edema

PCR and serology for SARS-CoV-2:

• RT-PCR negative, IgG and IgM positive serology

Inflammatory markers:

• CRP: 419 mg/L
• Ferritin: 3,275 lg/L (normal <322 µg/L)
• Procalcitonin: 164 lg/L (normal <50 µg/L)
• Troponin I: 2,030 ng/L (normal <57 ng/L)
• D-dimer: 2,722 ng/mL (normal <220 ng/mL)

• Vasopressor therapy, high-dose aspirin and broad-spectrum antibiotics in intensive care
• Immunomodulatory therapy was not given due to the good response to aspirin

The patient was admitted to the ICU and recovered over 10 days.

Fox et al., 2020^{Footnote 12}
United States
July 2020
The patient was a 31-year-old African American female
Her comorbidities included hypertension treated with lisinopril, diabetes with poor adherence to metformin and glizide, and obesity (body mass index [BMI]=36.1 kg/m2)
She had been discharged 12 days earlier after a hospitalization for COVID-19 disease with a positive RT-PCR

The patient was admitted for sudden fever 39.8ºC (duration not specified), tachycardia (120 beats/min), left-sided neck pain, nausea and vomiting
Inflammatory markers:

• D-dimer level of 2.48 nmol/L (normal <1.37 nmol/L)
• CRP levels 165 mg/L, then 580 mg/L (normal <9 mg/L)
• Ferritin level, 411.2 μg/L (normal 10-150 μg/L)
• Lactic acid level, 3.1 mmol/L (normal 0.3-2.0 mmol/L)
• Lymphopenia

One or more organs involved (pulmonary, cardiac, parotids, renal):

• CT scan of her neck showed bilaterally enlarged parotid glands and swelling in the posterior nasopharynx to oropharynx
• CT scan of her chest showed interval improvement of bibasilar ground-glass opacities, with cervical and anterior mediastinal lymphadenopathy
• Creatinine level 202.44 µmol/L (44.20-97.24 µmol/L); glomerular filtration rate 32 mL/min/1.73 m2 (>89 mL/min/1.73 m2)

PCR and serology for SARS-CoV-2:

• RT-PCR was positive 12 days prior to readmission
• MISC-A, RT-PCR was negative at readmission and serology was not performed

Patient developed hemodynamic instability and ventricular fibrillation during evaluation for hospital admission and died.

Jones et al., 2020^{Footnote 8}
United Kingdom
The date the study was conducted was not reported
September 2020
The patient was a 21-year-old male of African descent
The presence or absence of comorbidity was not reported

Fever and other signs or symptoms:

• Six days of fever
• Admitted for abdominal pain associated with constipation, anorexia
• Transient maculopapular palmar rash four days into illness
• Non-exudative conjunctivitis
• Cervical lymphadenopathy
• Cracked lips and prominent lingual papillae

PCR and serology for SARS-CoV-2:

• RT-PCR negative and serology was strongly positive, suggesting recent exposure to SARS-CoV-2

One or more organs involved:

• Rash
• Conjunctivitis
• Cervical lymphadenopathy
• Cracked lips and prominent lingual papillae

Inflammatory markers:

• Lymphopenia
• Elevated inflammatory and elevated troponin T
• Other infective and inflammatory conditions were excluded

• IVIG
• Methylprednisolone

The patient was discharged after a length of hospital stay of eight days.

Kofman et al., 2020^{Footnote 14}
United States
The date the study was conducted was not reported
September 2020
The patient was a 25-year-old female; her ethnicity was not reported
She was a non-smoker, did not use drugs, was not taking any prescription medications and had no known allergies
She had taken ibuprofen and acetaminophen over the previous week for symptom relief

Fever and other signs and symptoms:

• One week of low grade fever, weakness, dyspnea, fatigue
• Also developed mild cough, sore throat, vomiting, diarrhea and lymph node swelling

Upon admission:

• She was afebrile, with mild hypotension (blood pressure 98/56 mmHg)
• Oxygen saturation was normal on room air
• She appeared ill, with tender cervical lymphadenopathy
• Significant conjunctival injection without perilimbal sparing; injected, erythematous and cracked lips
• Tenderness to palpation in the left lower abdominal quadrant

One or more organs involved (renal, cardiac, digestive, ocular):

• Acute kidney injury: Creatinine 7.74 mg/dL (normal: 0.5-1.2 mg/dL) and leukocytosis
• Point-of-care echocardiogram revealed a dilated inferior vena cava and overloaded right ventricular pressure
• CT angiogram of the chest showed mild enlargement of the main pulmonary artery
• CT abdomen/pelvis demonstrated mild peripancreatic fat stranding, felt to possibly represent acute uncomplicated pancreatitis, as well as nonspecific bilateral perinephric fat stranding
• Conjunctivitis

PCR and serology for SARS-CoV-2:

• Positive RT-PCR and IgG serology

Inflammatory markers:

• CRP: 90 mg/L (normal: 0-10 mg/L)
• D-dimer: 960 mg/L (normal: 0-574 mg/L)
• Ferritin: 798 ng/ml (normal: 11-307 ng/mL)
• Lymphocytes: 3% (normal: 19-53)

• Aggressive fluid resuscitation and vasopressor
• IVIG, 2 g/kg split equally between hospital days 2 and 3
• Aspirin 325 mg daily for seven days
• Patient was offered remdesivir under an Emergency Use Authorization (EUA) basis, but declined
• At discharge she was prescribed a seven-day course of apixaban for COVID-19-associated coagulopathy per Emory University Hospital COVID-19 treatment guidelines

The patient was admitted to the ICU twice during her hospital stay. She was discharged on Day 5.

Lidder et al., 2020^{Footnote 9}
United States
May 2020
The case was a 45-year-old male with no comorbidities
Ethnicity was not reported

Fever and other signs and symptoms:

• Fever for five days, sore throat, diarrhea, eye redness, eyelid swelling and a diffuse rash including bilateral upper and lower eyelids

One or more organs involved (renal, cardiac, digestive, ophthalmologic):

• A transthoracic echocardiogram demonstrated global hypokinesis and a reduced ejection fraction of 40%
• CT imaging showed unilateral cervical lymphadenopathy with a lymph node measuring 1.8 cm
• Photophobia and swollen eyelids; no vision changes including blurry vision and eye pain
• Uncorrected near visual acuity was 20/20 bilaterally
• Bilateral superficial punctate keratitis, symmetric anterior chamber inflammation with 10-15 cells per high power field, and normal intraocular pressure. Dilated fundus exam was notable only for one small peripheral cotton wool spot in each eye
• Punch biopsy of his erythema multiforme-like rash
• Showed sparse superficial perivascular infiltrate of lymphocytes with neutrophils and scattered eosinophils, suggestive of toxic shock syndrome

Excluding other cause:

• Testing for myositis and HIV was negative
• An exhaustive rheumatologic workup, including ANA, RF, anti-CCP, anti-Smith, anti-dsDNA, p-ANCA/MPO, c-ANCA/PR3, was negative
• Blood cultures were negative

PCR and serology for SARS-CoV-2:

• Positive RT-PCR

Inflammatory markers:

• Lymphopenia
• Ferritin, CRP, ESR, D-dimer and troponin were elevated

• Ophthalmic lubricating therapy in addition to prednisolone acetate 1% eye drops four times daily for his photophobia in the setting of anterior chamber inflammation
• IVIG and an interleukin-6 (IL-6) inhibitor (tocilizumab) in addition to using a topical triamcinolone ointment for his diffuse rash

The length of hospital stay was not reported, but the patient did not demonstrate shock-like signs.

Moghadam et al., 2020^{Footnote 10}
France
The date the study was conducted was not reported
July 2020
21-year-old White male who did not smoke or use drugs
The presence or absence of comorbidity was not reported

Fever and other signs and symptoms:

• Fever and non-bloody watery diarrhea lasting for seven days
• Asymptomatic rash over his trunk and palms, consisting of erythematous round-shaped macules with a darker and raised rim, 1-3 cm in diameter
• Bilateral conjunctivitis
• Blood pressure 80/40 mmHg
• Respiratory rate was 38 breaths/min, and oxygen saturation was 97% on ambient air

One or more organs involved (cardiac, digestive, pleural):

• Electrocardiogram showed diffuse negative T-waves, and echocardiography displayed hyperkinetic left ventricle with normal ejection fraction, normal right cavities and dilated non-compressible inferior vena cava
• Thoraco-abdominal CT scan showed:
  • Signs of congestive heart failure
  • Bilateral pleural effusion
  • Wall thickening of the right colon
  • Respiratory function deterioration

PCR and serology for SARS-CoV-2:

• Negative RT-PCR and IgG-positive serology

Inflammatory markers:

• Lymphocytes: 900/mm3
• CRP: 365 mg/L
• Procalcitonin: 3.4 ng/mL
• Ferritin: 1,282 mg/L (normal <30)
• Lactate: 2.4 mmol/L (normal <1.6)
• Troponin level: 550 ng/L (normal <34)
• Cutaneous biopsy showed a slightly inflammatory infiltrate in upper dermis. Direct cutaneous immunofluorescence was negative

Exclusion of other causes:

• Extensive infectious inquiry and search for antinuclear antibodies were negative
• The rash was particular and diagnosis of erythema multiforma and subacute lupus erythematosus were ruled out

• Volume resuscitation
• Noradrenaline
• Antibiotics (i.e. ceftriaxone and amikacin)
• High-flow nasal oxygenation

The patient stayed in the ICU for eight days and recovered.

Sokolovsky et al., 2020^{Footnote 13}
United States
The date the study was conducted was not reported
June 2020
The case was a 36-year-old Hispanic female with no known comorbidity

Fever and other signs and symptoms:

• One week of fever, abdominal pain, vomiting and diarrhea
• Two days of a diffuse rash and arthralgias
• Tachycardia, tachypnea, hypotensive
• Classic phenotype of complete Kawasaki disease: bilateral nonexudative conjunctivitis mucositis with cracked lips, edema of the bilateral hands and feet, diffuse maculopapular rash and cervical lymphadenopathy

One or more organs involved (cardiac, digestive):

• CT angiogram of the chest: normal lung parenchyma and a trace right pleural effusion
• CT abdomen/pelvis illustrated mild circumferential gallbladder wall thickening and a small area of colitis
• Echocardiogram after treatment with IVIG revealed an ejection fraction of 65% with moderate tricuspid valve regurgitation. Subsequent coronary computed tomography angiography (CCTA) was normal except for a trace pericardial effusion

PCR and serology for SARS-CoV-2:

• Negative RT-PCR and IgG-positive serology

Inflammatory markers:

• CRP: 30 mg/dL (normal 0.0-0.9)
• D-dimer: 652 ng/mL (normal <318)

Exclusion of other cause:

• Anti-dsDNA, anti-Smith, anti-RNP, SSB, RF, CCP, ANCA, ASO and anti-Jo-1 antibodies were negative
• HIV and hepatitis panels were negative

• Fluid resuscitation for shock
• A single dose of aspirin 650 mg
• IVIG 2 g/kg
• Methylprednisolone 2 mg/kg for five days followed by a prednisone taper

The patient stayed at least six days in hospital and recovered.

Shaigany et al., 2020^{Footnote 11}
United States
The date the study was conducted was not reported
July 2020
The case was a 45-year-old Hispanic male
He had no known comorbidity

Fever and other signs and symptoms:

• Six days of fever, sore throat, diarrhea, bilateral lower extremity pain, conjunctivitis and diffuse exanthema
• Exposure to SARS-CoV-2 infection two weeks earlier
• Respiratory rate was 25-33 breaths per min
• Hypotension (systolic blood pressure 80-90 mmHg)
• Tachycardia with episodes of atrial fibrillation with rapid ventricular response
• Bilateral, nonexudative conjunctival injection
• Tender left neck swelling with palpable lymphadenopathy, periorbital edema with overlying erythema, lip cheilitis and targetoid erythematous papules and plaques with central duskiness involving the back, palms, neck, scalp, anterior trunk and upper thighs

One or more organs involved (renal, cardiac, digestive, ophthalmologic):

• CT of the neck revealed inflammation and edema involving the bilateral lower eyelid and pre-septal space, as well as sub-occipital reactive lymphadenopathy
• Electrocardiogram demonstrated:
  • ST elevations in the anterolateral leads
  • Global hypokinesis of the left ventricular wall with a mild to moderately reduced ejection fraction of 40%
• Diffuse conjunctivitis with chemosis as well as the presence of inflammatory cells within the anterior chamber, indicative of uveitis
• A 4-mm punch biopsy of the skin was performed on a papule on the back, with histology revealing rare intraepithelial collections of neutrophils with necrotic keratinocytes and a sparse interstitial, mixed-cell dermal infiltrate with vacuolar interface changes

PCR and serology for SARS-CoV-2:

• Positive RT-PCR

Inflammatory markers:

• Lymphopenia (0-700 lymphocytes per µL)
• ESR of 120 mm/hour
• Ferritin of 21,196 ng/mL
• CRP of 546.7 mg/L
• D-dimer of 2,977 ng/mL
• Procalcitonin of 31.79 ng/mL
• Interleukin-6 (IL-6) 117 pg/mL
• Troponin 8·05 g/mL

Exclusion of other causes:

• HIV-1 and HIV-2 antibodies were negative
• Bacterial blood cultures were negative

• Therapeutic dose low molecular weight heparin
• IVIG of 2 g/kg over two days
• A single intravenous dose of the interleukin-6 (IL-6) inhibitor tocilizumab (400 mg)

The patient was in hospital for eight days and did not require vasopressor support or ICU level of care, and recovered.

• Rash
• Bilateral non-purulent conjunctivitis
• Signs of muco-cutaneous inflammation (in the mouth or on the hands or feet)
• Hypotension or shock
• Myocardial dysfunction, pericarditis, valvulitis or coronary abnormalities (including echocardiogram findings or elevated troponin/NT-proBNP)
• Coagulopathy (increased prothrombin time, activated partial thromboplastin time, elevated D-dimers)
• Acute gastrointestinal problems (diarrhea, vomiting or abdominal pain)