[version 1; peer review: 2 approved with reservations]
No competing interests were disclosed.
The first cases of acute respiratory syndrome caused by COVID-19 were diagnosed in Hubei, China, in December 2019. The high rate of infectivity of the microorganism has triggered a pandemic. Symptoms include dry cough, headache, dyspnea, diarrhea, or fever. However, COVID-19 may also cause respiratory failure, kidney failure, cardiac injury, and central nervous system damage. Patients with comorbidities such as hypertension, obesity, or diabetes are at a higher risk of developing severe symptoms
Although the pathophysiology of the virus remains unknown, several studies have associated COVID-19 with a cytokine storm quite similar to that occurring in hemophagocytic syndrome (macrophage activation syndrome). This syndrome is characterized by elevated levels of interleukins (IL-1b, IL-6, IL-10, IL-12), interferon (alpha, gamma), and tumor necrosis factor (TNF-alpha); hypertriglyceridemia; hyperferritinemia; hemophagocytosis in the bone marrow, cerebrospinal fluid, or lymph nodes; and manifests in the form of fever, hepatosplenomegaly, hemorrhagic diathesis, cutaneous rash and alterations of consciousness
The myocardial depressant effect of cytokines, an oxygen deficit generated by a prothrombotic state and coronary vasospasms could cause cardiac injury and dysfunction in other organs.
IL-6, cardiac troponins (cTnI/T), and the amino-terminal fraction of the cerebral natriuretic propeptide (NT-proBNP) have been documented to be elevated in patients with cardiac failure secondary to COVID-19
Viral myocarditis is a widely described condition, with symptoms such as heart failure. It usually develops within one to three weeks of COVID-19 infection. Potential COVID-19 myocarditis therapies are based on inotropic drugs and extracorporeal life support
Our case is unique because the differential diagnosis was quite difficult and interesting. First, it seemed the patient had septic shock and a lymphoproliferative syndrome. Then we thought about hemophagocytic syndrome as well, so he is probably one of the few patients with such an exhaustive study at the immune and hematological level, which could help to understand COVID-19.
Besides that, we follow therapeutic guidelines that differ from the usual, using levosimendan as an inotropic agent
The patient was a 16-year-old Spanish adolescent, Caucasian, with no allergies, with extrinsic asthma treated with corticosteroids and aerosols occasionally. He has no relevant past interventions and no medical, family or psychosocial history (including genetic) of interest. He presented with general discomfort, asthenia and fever (38°C) for three days and was treated with paracetamol 1g/8 hours and azithromycin 500mg/24 hours for three days at home. After seven days, he came to the emergency department with persistence of symptoms, shortness of breath, arthromyalgia and diarrhea.
Physical examination revealed a bad general condition. Blood pressure was 70/30 mmHg, heart rate was 110 bpm, respiratory rate was 18 bpm, and axillary temperature was 38.5°C. Lung auscultation found bibasilar crackles and heart auscultation found no murmurs. He had hepatosplenomegaly, oliguria, no edemas, no cutaneous rash and no arthritis. He had diuresis of 170 ml in 12 hours. The results of laboratory testing were: white blood cell count 10200
9/L, with 84.2% neutrophils, red blood cell count 4.2
12/L, hemoglobin 12.5 g/L, platelet count 104000
9/L, serum C-reactive protein level 269.4 mg/L, alanine aminotransferase level 81 U/L, aspartate aminotransferase level 71 U/L, total bilirubin level 3.30 mg/dL, direct bilirubin level 2.73 mg/dL, cardiac troponin I 1135 pg/ml, blood urea nitrogen 48 mmol/L, creatinine 2.72 μmol/L, erythrocyte sedimentation rate of 12 mm/h, procalcitonin 1.96 ng/ml., arterial pH of 7.32, pCO2 of 50.2 mmHg, pO2 of 68 mmHg, HCO
3 23 mmol/L, SO2 94%, lactic acid 2.2 mmol/L, ferritin 655.4 ng/mL, triglycerides 161 mg/dL, uric acid 11.3 mg/dL, prothrombin activity 64.7%, international normalized ratio 1.28, activated partial thromboplastin time (aPTT) 28.9 seconds, aPTT ratio 1.16 and D-dimer 7.500 ng/ml. The evolution of laboratory parameters during admission to the Intensive Care Unit (ICU) is shown in
| ICU admission | Three days after admission | Six days after admission | ICU discharge | |
|---|---|---|---|---|
| Leukocytes | 10600 μL −1 | 31280 μL −1 | 25320 μL −1 | 12600 μL −1 |
| Neutrophils | 8720 μL −1 | 27730 μL −1 | 21190 μL −1 | 9348 μL −1 |
| CRP | 252.3 mg.l -1 | 92.9 mg.l -1 | 46 mg.l -1 | 12.2 mg.l -1 |
| Procalcitonine | 1.96 ng.l -1 | 23.22 ng.l -1 | 0.27 ng.l -1 | 0.1 ng.l -1 |
| Lactic acid | 2.2 mmol.l -1 | 2.7 mmol.l -1 | 1.1 mmol.l -1 | 1.2 mmol.l -1 |
| Hemoglobin | 13.2 g.dl -1 | 9.4 g.dl -1 | 10.5 g.dl -1 | 10.2 g.dl -1 |
| Platelets | 105000 μL −1 | 248000 μL −1 | 584000 μL −1 | 874000 μL −1 |
| Ferritin | 655.4 ng.ml -1 | 402 ng.ml -1 | 497 ng.ml -1 | 521.6 ng.ml -1 |
| D-dimer | 7172 ng.ml -1 | 4103 ng.ml -1 | 2724 ng.ml -1 | 833 ng.ml -1 |
| Fibrinogen | 546.8 mg.dl -1 | 316.8 mg.dl -1 | 323.7 mg.dl -1 | 286.7 mg.dl -1 |
| LDH | 188 U.l -1 | 359 U.l -1 | 248 U.l -1 | 136 U.l -1 |
| CK | 22 U.l -1 | 49 U.l -1 | 34 U.l -1 | 15 U.l -1 |
| Troponin I | 1135 ng.l -1 | 308.4 ng.l -1 | 130.3 ng.l -1 | 12.3 ng.l -1 |
| Creatinine | 2.72 mg.dl -1 | 1.41 mg.dl -1 | 0.65 mg.dl -1 | 0.61 mg.dl -1 |
| Bilirubin | 2.9 mg.dl -1 | 0.8 mg.dl -1 | 0.7 mg.dl -1 | 0.5 mg.dl -1 |
ICU, intensive care unit; CRP, C-reactive protein; LDH, lactate dehydrogenase; CK, creatine kinase.
A nasopharyngeal swab and reverse transcriptase-polymerase chain reaction (RT-PCR) for COVID-19 was negative, but COVID-19 serology was IgM negative and IgG positive. Microbiological screening (urine, blood, sputum and stool culture), serological tests (virus, parasites, fungi and bacteria), and a Mantoux test were carried out. His thoracoabdominal CT scan showed multiple para-aortic and peri-pancreatic lymphadenopathy (compatible with lymphoproliferative syndrome as the most likely diagnosis) and acute respiratory distress syndrome (ARDS). There was no sign of pulmonary thromboembolism, but there were signs of pulmonary hypertension. He was admitted to the ICU and treated with broad spectrum antibiotics (imipenem 1g/8h, linezolid 600mg/12h) and a low dose of norepinephrine (0.05 mcg/kg/min).
An investigation of lymphoproliferative syndrome considering the possibility of hemophagocytic syndrome secondary to COVID-19 was carried out, including autoimmune tests. Protein electrophoresis showed an inflammatory pattern and a direct Coombs test was negative. A bone marrow biopsy showed reactive cells, without atypical cellularity, discarding lymphoproliferative or hemophagocytic syndrome. Tests for autoimmune diseases revealed a low level of C3 and positivity for lupus anticoagulant. The rest of the antibody tests were negative.
Microbiological screening, serological test and Mantoux were all negative, supporting the theory of an exaggerated systemic inflammatory response due to COVID-19. Septic shock was ruled out, so we decided to withdraw antibiotics. Only a rectal swab was positive for COVID-19.
During his time in hospital, the patient presented with acute confusion and agitation. He had no meningeal signs on examination. Cranial CT scan was normal and symptoms remitted within 24 hours.
An electrocardiograph showed atrial fibrillation and diffuse T wave inversion. Transthoracic echocardiography (TTE) was performed regularly, due to elevated cardiac enzymes. The first TTE was normal, but on the third day of admission demonstrated moderate biventricular dysfunction that progressed to severe in the following 24 hours, and atrial fibrillation. The evolution of echocardiographic parameters during admission to the ICU is shown in
From the beginning our patient was treated with a nasal cannula at 3 liters/minute for five days and a venturi mask at 40% FiO2 for four days. Also, broad spectrum antibiotics (at the beginning, 1g/8h imipenem and 600mg/12h linezolid for six days, and on the third day of admission, 500mg/24h daptomycin and 200mg/24h fluconazole were added to the regimen) and a low dose of norepinephrine (0.05 mcg/kg/min) were administered.
When the possibility of a septic shock was ruled out, antibiotics were withdrawn and 8mg/24 hours dexamethasone was started to try to contain the cytokine storm due to COVID-19. The dose was increased to 12 mg when he suffered with confusion, agitation and heart failure. The patient was treated with adrenalin up to 0.1 mcg/kg/min, 12.5mg/24 hours levosimendan and 20mg/8-12 hours furosemide for eight days. A bolus of 150 mg amiodaron followed by an infusion of 600mg in 24 hours was administered when atrial fibrillation was targeted. He was given enoxaparin 60mg/24 hours during the first days and then it was increased to 60mg/12 hours.
A new TTE that was performed four hours after levosimendan was initiated showed a moderate improvement in left ventricular function and a slight improvement in right ventricular function. In 12 hours, the cardiac function returned to normal and sinus rhythm was recovered (
| Day 3 | Day 4 | 4 hours after levosimendan | 12 hours after levosimendan | 24 hours after levosimendan | ICU discharge | |
|---|---|---|---|---|---|---|
| LVEF | 46% | 32% | 40% | 45% | 50% | 65% |
| LVIDD | 59 mm | 56 mm | Normal | Normal | 53 mm | 53 mm |
| SPAP | 55-60 mmHg | 45 mmHg | 40 mmHg | 40 mmHg | 35 mmHg | 35 mmHg |
| S Wave | 15 cm/seg | 8 cm/seg | 12 cm/seg | 15 cm/seg | 15 cm/seg | 15 cm/seg |
| TAPSE | 25 mm | 11 mm | 17 mm | 23 mm | 23 mm | 17 mm |
LVEF, left ventricular ejection fraction; LVIDD, left ventricular internal diameter in diastole; SPAP, pulmonary arterial systolic pressure; S wave; systolic wave; TAPSE, tricuspid annular plane systolic excursion; ICU, intensive care unit.
Hemodynamic support therapy was withdrawn, and oxygen therapy, furosemide and dexamethasone were progressively reduced. He didn´t have any adverse events with the medication; it was well tolerated.
In a few days, the clinical picture resolved and the patient was discharged to the Internal Medicine ward. The evolution of his condition was very favorable. He was afebrile, hemodynamically stable, with good food tolerance and without other clinical symptoms. Microbiological screening was repeated by Internal Medicine and a stool culture was positive for group B Salmonella species. The patient had no symptoms, but ciprofloxacin was administered for seven days and then he was discharged hemodynamically stable, eupneic and with oxygen saturation of 99% with oxygen supply of 0.28%. Two weeks later he left the hospital.
A timeline with information from the current episode of care is shown in
| Initial patient assessment | - A 16-year-old Spanish adolescent, Caucasian, no allergies, extrinsic asthma treated with corticosteroids and aerosols occasionally.
|
| - Blood pressure 70/30 mmHg, heart rate 110 bpm, respiratory rate 18 bpm, axillary temperature 38.5°C.
|
|
| - General discomfort, asthenia and fever (38°C) for three days.
|
|
| Diagnostic evaluation and therapeutic interventions | - Nasopharyngeal swab RT-PCR and serology of COVID-19.
|
| - Paracetamol 1g/8h and azithromycin 500mg/24h for three days.
|
|
| Outcomes and follow-up | - After a good recovery in ICU, the patient was discharged to the Internal Medicine ward.
|
| - In a follow-up visit to the Internal Medicine clinic he remained asymptomatic and without sequelae.
|
CT, computed tomography; RT-PCR, reverse transcriptase polymerase chain reaction; ICU, Intensive Care Unit.
The Systemic inflammatory response syndrome (SIRS) may be caused by sepsis of bacterial origin, but sometimes it is difficult to substantiate and the differential diagnosis from non-infectious conditions is frequently a challenge. Definitive diagnosis requires isolation of a microorganism, but occasionally this is not possible
In this case, cardiac failure especially contributed to the severity of the patient’s condition. Myocarditis is an inflammatory disease of the heart muscle caused by viruses mainly, although bacteria, toxic drugs and autoimmune diseases can produce it too. The exacerbation of the inflammatory response along with the cytokine storm and its associated cardio-depressor and prothrombotic effects could be the cause of alterations in the coronary circulation (microcirculation and vasospasm), myocardial dysfunction, and increased oxygen consumption
The patient was treated with adrenaline, diuretics, and levosimendan. He was also receiving anti-inflammatory treatment with dexamethasone, for suspicion of a possible immunological disease secondary to COVID-19
When he was discharged to the Internal Medicine ward, he continued to show favorable progress and clinical improvement. However, they repeated the stool culture again and it was positive for Salmonella species and treated with ciprofloxacin, although the patient remained asymptomatic. In subsequent check-ups the patient had no sequelae of the disease and cardiac magnetic resonance imaging was performed, which was normal. This makes us suspect that the Salmonella infection was probably acquired in hospital and it was not the cause of myocarditis, although we cannot completely rule it out.
All data underlying the results are available as part of the article and no additional source data are required.
Written informed consent for publication of their clinical details was obtained from the patient.
The authors bring an interesting case of a 16-year-old boy with severe COVID-19. Although the authors claim the cytokine storm was an underlying mechanism, there is no clear evidence that this was the scenario in described patients (the authors did not measure plasma cytokine concentration).
The following sentence in the Introduction section is not clear: "
The patient's asthma had been treated with corticosteroids and aerosols occasionally. Please provide the treatment regimen and doses in more detail. Could asthma (and corticosteroids) have been a risk factor for the patient described? Please discuss.
Was SpO2 measured by pulse oximetry immediately at admission? Please provide data on the patient's state of consciousness at admission. Were there any physical signs of dehydration in the patient upon admission (skin turgor, dry mucous membranes)? Please describe the patient's diarrhea (duration, stool frequency, number of stools). Please show normal laboratory values in parentheses for each parameter. Please provide data on the kit/device used for RT-PCR.
The lack of nasopharyngeal RT-PCR positivity with rectal swabs being positive is the most intriguing detail, but the authors did not discuss it. Please include it in the discussion. What are the potential causes of such findings? Is there any role of ACE2 distribution (see and refer to:
The discussion section should be more comprehensive, including consideration of the mechanisms of cardiac affection and arrhythmias described (see above).
Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?
Partly
Is the case presented with sufficient detail to be useful for other practitioners?
Yes
Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?
Partly
Is the background of the case’s history and progression described in sufficient detail?
Yes
Reviewer Expertise:
COVID-19, heat shock proteins, oncogenesis, autoimmunity, neuroscience
I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.
This case report is well described, at times almost redundant. The description of the clinical case is interesting and complete in all information. However, the discussion should be revised because it lacks a very important etiological entity talking about this topic which is the MIS-C and the most important works regarding this topic are not even mentioned: Feldstein
Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?
Yes
Is the case presented with sufficient detail to be useful for other practitioners?
Yes
Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?
No
Is the background of the case’s history and progression described in sufficient detail?
Yes
Reviewer Expertise:
Infectious Disease
I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.