The National Institutes of Health (NIH) has awarded 8 new research grants to help identify children who are at high risk of contracting multisystem inflammatory syndrome in children (MIS-C), a severe result of COVID-19 in some children. 

The studies will include how genetic, immune, viral, environmental, and other conditions influence the level of severity of COVID-19, and the chance of it progressing to MIS-C in certain cases. The awards are a part of the Rapid Acceleration of Diagnostics (RADx) Radical (RADx-rad) program that supporrs non-traditional approaches and new uses of existing technologies to address gaps in COVID-19 testing and surveillance.

The studies, which will be using artificial intelligence and machine learning, will be studying genes, immune system proteins, and other biomarkers, examine how the virus interacts with the body and how the immune system responds to it. The awardees and their project names are:

Jane C Burns, University of California, San Diego
Diagnosing and predicting risk in children with SARS-CoV-2-related illness

Cedric Manlhiot, Johns Hopkins University, Baltimore
A data science approach to identify and manage MIS-C associated with SARS-CoV-2 infection and Kawasaki disease in pediatric patients

Ananth V Annapragada, Baylor College of Medicine, Houston
Artificial intelligence COVID-19 risk assessment for kids

Audrey R Odom John, Children's Hospital of Philadelphia
Diagnosis of MIS-C in febrile children

Usha Sethuraman, Central Michigan University, Mount Pleasant
Severity predictors integrating salivary transcriptomics and proteomics with multi neural network intelligence in SARS-CoV2 infection in children

Juan C Salazar, Connecticut Children's Medical Center, Hartford
Identifying biomarker signatures of prognostic value for MIS-C

Charles Yen Chiu, University of California, San Francisco
Discovery and clinical validation of host biomarkers of disease severity and MIS-C with COVID-19

Lawrence Kleinman, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
COVID-19 Network of networks expanding clincial and translational approaches to predict severe illness in children

Articles

The National Institutes of Health award 8 research grants to develop ways to identify children at high risk for multi system inflammatory syndrome I children (MIS-C).

NIH funds 8 new studies on COVID-19 related MIS-C in children

Happy summer! As we move into the now fourth month of the COVID-19 pandemic, we have had to adjust to new ways of providing comprehensive care to all our patients. The pandemic has led to some unintended consequences in our ability to provide this care, the most critical being the immunization of infants and children in a timely manner.

Studies have shown that up-to-date vaccine status for the recommended childhood vaccines has significantly decreased since the start of the pandemic, with less than 50% of infants and children in many areas of the United States being reported as current on their vaccines. This decrease has been most striking for infants and children enrolled in Medicaid insurance programs. The marked drop in immunization rates has a major impact on herd immunity and leaves these infants and children susceptible to vaccine-preventable diseases such as measles and pertussis. As pediatric health care providers, we need to make a concerted effort to get patients back into the office for their vaccines against all the vaccine-preventable diseases.

COVID-19 infection for many children is milder than that seen in the adult population. However, as we continue to learn more about COVID-19, there are new issues that have a significant impact on our ability to care for our patients. The emergence of multisystem inflammatory syndrome in children (MIS-C) has demonstrated that COVID-19 infection in some children can be serious and life threatening, and that has added a sense of urgency in the diagnosis and treatment of these patients.

This issue of Contemporary Pediatrics is dedicated to Infectious Disease, with many articles exploring different aspects of COVID-19 infection in infants and children and intended to provide health care providers with guidance in diagnosis and management. The articles focusing on COVID-19 include:

—This article is an interesting opinion piece addressing the impact that the presence of fever may have in recovery from COVID-19 infection.

Multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19

—Here is a summary of information presented in a most successful webinar on MIS-C that provides comprehensive guidance for the pediatric practitioner on the diagnosis and treatment of this potentially life-threatening syndrome.

AAP guidance: Managing infants born to mothers with COVID-19

—This document provides very practical guidance on the recommended testing and management of neonates born to mothers with COVID-19 in a variety of different settings.

Even as we continue to work through the COVID-19 pandemic, remember to get outside once in a while and enjoy the sunshine. Summer really can be the best time of the year.

Please stay safe and well. I welcome your suggestions, comments, and questions.

The coronavirus pandemic keeps complicating the care of children in critical ways.

COVID-19: It’s not the same-old same old!

A healthy 11-day-old male infant is brought to the pediatric clinic for evaluation of rash. The rash started with a 2-mm papule on the left medial epicanthal fold 4 days before the clinic visit (Figure 1). The mother had scratched it, trying to pop the papule. The next day, the infant developed multiple erythematous papules and pustules medial to the left eye with sparing of the eye. A day before coming to the clinic, the rash had spread to the upper left eyelid and the nasal bridge (Figure 2).

The patient is asymptomatic and without fever or any sick contacts. The rest of his skin is clear. His mother has no history of genital herpes or oral lesions. No one has kissed the baby. The patient is being fed both breast milk and formula, with vitamin D supplementation. He usually has 6 to 7 wet diapers a day and passes stools around 4 to 5 times a day.

The patient was born via repeat cesarean delivery at 39 weeks’ gestation to a 39-year-old gravida 3 para 2 woman. The mother’s laboratory was unremarkable, including negative tests for human immunodeficiency virus (HIV), hepatitis-B surface antigen, and syphilis screen, group B 

, gonorrhea, and chlamydia. The mother had no active herpetic lesions during pregnancy.

The rupture of the membranes was at the time of the cesarean delivery. Apgar scores were 9 and 9 at 1 and 5 minutes, respectively. Postnatal resuscitation was not required. Both maternal grandparents have diabetes mellitus type 2. The mother lives with 2 families in the house, the grandfather smokes outside the house, and there are no animals in the house. Her immunizations are up-to-date.

The physical examination revealed normal vital signs and a rash on the patient’s face comprised of multiple 1-mm to 2-mm pustules on erythematous base involving the medial upper and lower eyelids bilaterally (Figure 3). The involvement was more on the left side, bridge of the nose, and contiguous lower mid-forehead. There was no discharge or any oozing from the rash. There were no oral or conjunctival lesions. The rest of the examination was unremarkable.

Some articles have described neonatal cephalic pustulosis as a separate entity from neonatal acne, based on the absence of comedones and the presence of pustules surrounded by an erythematous halo.

 Other differential diagnoses (Table) are as follows:

Erythema toxicum neonatorum is rarely present at birth and may begin after 24 hours of life. It can appear anytime from birth to 2 weeks and usually lasts for several days to weeks. Rash is polymorphous and usually does not involve the palms and soles.

 Scrapings of pustules will reveal a large number of eosinophils. No treatment is necessary.

Transient neonatal pustular melanosis is more common in blacks and generally present at birth but rarely appears after birth. It usually resolves within 24 to 48 hours and can involve the palms and soles. Scraping of the pustules can show neutrophils. No treatment is necessary.

Staphylococcal pustulosis is a common bacterial cause of pustular skin lesion that is usually localized to the periumbilical area, neck fold, and diaper area.

 It presents as cutaneous erythema followed by peeling of skin and can cause significant complications and require prompt treatment. Gram stain of the scrapings can detect the bacteria. Treatment with appropriate antibiotics is recommended to reduce mortality.

Herpes simplex virus (HSV) is usually accompanied by a history of HSV-2 in the mother. It generally manifests as grouped vesicles on erythematous base present anywhere on the body but mostly localized to the eye, skin, and mouth. Tzanck preparation can show multinucleated cells but a viral culture is the gold standard. Treatment with systemic acyclovir is recommended to prevent disseminated or central nervous system (CNS) spread.

Eosinophilic pustulosis presents as recurrent white-to-yellow pustules on the scalp or forehead that usually crust within 2 to 3 days but can last for years. There is some association with immunodeficiency. Giemsa stain can be done, which shows eosinophils predominance. It can be treated with topical corticosteroids or erythromycin.

Acropustulosis of infancy presents as a chronic recurrent eruption of vesicles and pustules on the hands and feet usually lasting for hours after birth, but it can occur anytime during infancy. The lesions usually disappear in 10 days but can reappear every month for the first 3 years. These erythematous papules can progress to intensely itching pustules in other parts of the body and usually require symptomatic treatment.

Miliaria pustulosis can be divided into 2 types—miliaria rubra and miliaria crystalline—within the first week of life. It presents as a polymorphous rash on the face, trunk, and intertriginous areas. It is precipitated in warm weather as excess sweating can cause obstruction of the eccrine duct. No treatment is necessary but cool baths and breathable fabrics are helpful.

Congenital dandidiasis can present at birth or may appear after a few days as macules, papules, and pustules over the body but sparing the diaper area. It usually involves the palms and soles and can cause yellowish discoloration of fingernails with paronychia. Treatment is topical antifungal.

The infant was seen in the clinic and subsequently admitted to the hospital due to suspected herpes simplex infection (Figure 4). He was started on intravenous acyclovir 60 mg/kg/day divided Q8 hourly. Bacitracin ointment was applied topically on the rash twice a day. The viral culture was done from the wound specimen. Ophthalmology consultation was obtained, and they confirmed that there was no involvement of the eye. The following tests were sent: herpes viral PCR, Tzanck smear, and direct fluorescent antibody (DFA) test.

On the second day of admission, the pustules were larger and the red base more confluent (Figure 5). Because of concern for HSV, the Infectious Disease service was consulted and upon their suggestion fungal stain for potassium hydroxide (KOH) and cultures were sent. Intravenous acyclovir was continued and bacitracin ointment was replaced with miconazole. Final results showed negative fungal and viral cultures, the KOH stain was negative, and HSV PCR was not detected. Acyclovir was discontinued. The rash started to improve (Figure 6) and the patient was discharged home on miconazole ointment.

Diagnosis of neonatal cephalic pustulosis

Neonatal cephalic pustulosis usually develops during the first month of life and is characterized by uniform small papules and pustules on a red base involving the face and neck. It is related to the stimulation of sebaceous glands by maternal androgens.

 Histologic examination demonstrates an inflammatory infiltrate of primarily neutrophils and yeasts of the genus 

 Some have suggested that neonatal cephalic pustulosis results from an inflammatory response to this yeast. Higher colonization is associated with increased severity of pustulosis.

 Most cases resolve spontaneously in several weeks without treatment but treatment with anti-yeast topical therapy may hasten resolution.

Neonatal cephalic pustulosis can be differentiated from neonatal acne by the presence of monomorphic lesions, the absence of comedones or nodular lesions, and the absence of a follicular distribution. The following criterion was suggested to define this entity: (a) pustules on face and neck; (b) age at onset, younger than 1 month; (c) isolation of 

 by direct microscopy in pustular material; (d) elimination of other causes of pustular eruption; (e) response to topical ketoconazole therapy.

Treatment usually is not required as neonatal cephalic pustulosis is self-limiting. In severe cases, ketoconazole cream 2% or other topical antifungal agents and hydrocortisone cream 1% can be used.

The patient was reevaluated in clinic a week after hospital discharge, and the rash was almost completely resolved with a fine ring of desquamation (Figure 7). Routine visits after that showed no residual rash.

1. Bernier V, Weill FX, Hirigoyen V, et al. Skin colonization by 

 species in neonates: a prospective study and relationship with neonatal cephalic pustulosis

2. Zuniga R, Nguyen T. Skin conditions: common skin rashes in infants. 

3. Melish ME. Staphylococcal infections. In: Feigin RD, Cherry JD, eds. 

Textbook of Pediatric Infectious Diseases

; Philadelphia, PA: WB Saunders;1987:1260-1291.

4. Mogre DA. Generalised staphylococcal pustulosis on a neonate: a case report. 

5. Rapelanoro R, Mortureux P, Couprie B, Maleville J, Taieb A. Neonatal 

6. Niamba P, Weill FX, Sarlangue J, Labrèze C, Ckouproe B, Taieh A. Is common neonatal cephalic pustulosis (neonatal acne) triggered by 

7. Howard RM, Frieden IJ. Vesicles, pustules, bullae, erosions, and ulcerations. In: Eichenfield LF, Frieden IJ, Mathas EF, Zaenglein AL, eds. 

. 3rd ed. London: Saunders, 2015;111-139.

A healthy 11-day-old male infant is brought to the pediatric clinic for evaluation of rash. The rash started with a 2-mm papule on the left medial epicanthal fold 4 days before the clinic visit. A day before coming to the clinic, the rash had spread to the upper left eyelid and the nasal bridge. What's the diagnosis?

Newborn’s rash involves eyes and nose

Since the first report of an outbreak of respiratory disease in Wuhan, China, in December 2019 caused by a novel coronavirus (SARS CoV2), coronavirus disease (COVID-19) has reached pandemic proportions. As of June 6, 2020,

 there were 6,663,304 cases and 392,802 deaths reported worldwide, with 1,891,690 cases and 109,192 deaths reported in the United States. Children and infants have been relatively spared from severe COVID-19, with pediatric cases accounting for less than 2% of COVID hospitalizations.

However, in late April, reports began to emerge of a multisystem inflammatory syndrome in children (MIS-C) related to SARS-CoV-2 infection. The Centers for Disease Control and Prevention (CDC) established the following definition for MIS-C:

An individual aged 21 years and younger with fever for 1 or more days, laboratory evidence of inflammation, and illness requiring hospitalization with multisystem (2 or more) organ involvement (cardiac, renal, hematologic, gastrointestinal, dermatologic, neurologic), AND

Evidence of current or recent SARS-CoV-2 infection by reverse transcription polymerase chain reaction (RT-PCR), serology or antigen test, or exposure to a suspected or confirmed COVID-19 case within the 4 weeks prior to the onset of symptoms.

This definition provides a starting point for addressing this newly described hyperinflammatory syndrome with COVID-19, but it is also overly broad without adequately defining the nature of the multisystem involvement and only requiring 1 or more days of fever. The very elevated inflammatory (C-reactive protein [CRP], ferritin, triglycerides) and myocardial markers (N-terminal-pro B-type natriuretic peptide [NT-proBNP] and troponin) and associated thrombocytopenia and lymphopenia do appear to be useful in consideration of a child with possible MIS-C.

Initial series of cases compatible with the diagnosis of MIS-C have been published from Europe. Riphagen and colleagues described 8 previously healthy children aged 4 to 14 years from Evelina London Children’s Hospital who presented with hyperinflammatory shock and features similar to atypical Kawasaki disease (KD), KD shock syndrome (KDSS), or toxic shock syndrome (TSS) in mid-April 2020.

 Of the 8 cases, 6 were children of African-Caribbean descent, most were teenagers, and 5 were males. All tested negative for SARS-COV2 by PCR but all had detectable antibodies to the virus.

Prominent clinical features in these cases included high fevers, gastrointestinal symptoms, and shock requiring mechanical ventilation in 7 of the cases, and a lack of respiratory symptoms. Laboratory parameters were notable for elevated CRP, procalcitonin, ferritin, D-dimers, triglycerides, troponin, and NT-proBNP. All were treated with intravenous immunoglobulin (IVIG), pressors, and antibiotics. Six received aspirin. One death occurred in a child with refractory shock and an arrhythmia requiring extracorporeal membrane oxygenation (ECMO) who developed a cerebrovascular infarct. One child developed a giant coronary aneurysm. The others were discharged from intensive care in 4 to 6 days and recovered.

A series of 10 children aged 3 to 16 years (mostly teenagers) from Bergamo, Italy, presenting between February 18 and April 20, 2020, with what the authors labeled as severe Kawasaki-like disease was published in the 

 By definition, these children met the 2017 American Heart Association criteria for KD or incomplete KD with 5 or more days of fever, compatible rash, and mucous membrane findings, but the overall picture was not consistent with classic KD.

Additionally, diarrhea was reported at presentation in 6 of the 10 children. Two of the children were positive for SARS-CoV2 by PCR; 8 were positive for SARS-CoV2 antibodies; and 2 were negative by PCR and serologic testing. Laboratory testing was notable for increased inflammatory markers, lymphopenia and thrombocytopenia (8/10 for each), increased triglycerides, increased ferritin, elevated proBNP (10/10), and troponin (5/9 tested). Five of the 10 presented in shock and 5 met criteria for macrophage activation syndrome (MAS). All received IVIG and aspirin; 8 of 10 were administered adjunctive steroids. All the children recovered and continue to be followed for development of coronary aneurysms.

More recently, a large French series of 35 patients with MIS-C was recently published in 

 These previously healthy children were cared for at 1 Swiss and 12 French hospitals from March 22 to April 30, 2020, utilizing the criteria of fever, cardiogenic shock or left ventricular ejection fraction (LVEF) less than 50%, and elevated CRP. The median age was 10 years with only 1 of 35 aged younger than 5 years and 19 of 35 aged from 11 to 16 years. SARS-CoV-2 testing in this group was positive in 31 of 35, with RT-PCR positive in 14 of 35 (12 nasopharyngeal and 2 fecal) and positive serology in 30 of 35 including IgG positive in 28. In 13 of 35 patients there was a recent family member with viral symptoms.

The clinical features of these 35 patients included fever and asthenia in all; 83% had abdominal pain associated with diarrhea and/or vomiting; 65% had respiratory distress; and some had rash or lip inflammation. None met the diagnostic criteria for KD. Twenty-nine of 35 were admitted to the pediatric intensive care unit (PICU) with cardiogenic shock, two-thirds were mechanically ventilated, and 10 of 35 received circulatory assistance with venous-arterial ECMO.

Echocardiographic features included 10 of 35 children with LVEF less than 30% and 25 of 35 with LVEF between less than 30% to 50%. Global left ventricular hypokinesis was present in 31 of 35 and segmental left ventricular hypokinesis in 3 more. The evolution of LVEF impressively improved rather quickly, with mean (and SD) LVEF equal to 32% (9%) at baseline in all 35, improved on day 3 to 52% (10%) in 23, and on day 7 to 60% (6%) in 34 patients. Six of 35 patients had a coronary artery 

 score greater than 2.0, although 5 of these 6 involved the left main coronary artery (of little significance per recent guidelines) and 1 involved the right coronary artery. No coronary aneurysms were detected.

Laboratory features of these patients were very striking and included median CRP of 24 mg/dL (range 15-31); high-sensitivity (hs) troponin of 347 ng/mL (range 186-1267; normal, <26 ng/mL); NT-proBNP, 41,000 pg/mL (range, 35,000-52,000; normal, <300 pg/mL); D-dimers, 5284 ng/mL (range 4000-9000; normal, <500 ng/mL); and interleukin (IL)-6, 135 pg/mL (range 87-175; normal, <8.5 pg/mL).

Treatment of the 35 patients included 28 who received inotrope(s), 25 treated with IVIG, 12 who received IV steroids (as in patients with high-risk KD), 3 received anakinra, and 25 of 35 were treated with heparin. The outcomes of the 35 children are remarkable in that all survived after a median 7-day PICU stay and 10-day total hospital stay. Twenty-five of 35 were at home with LVEF greater than 60% at day 7 with an additional 3 children at home with LVEF greater than 45%. LV function normalized in 25 of 35 patients at a mean of 2.2 days. No patients experienced thromboses or emboli.

A second similar French series of 21 patients included 12 (57%) who had at least 1 parent from sub-Saharan Africa or a Caribbean island.

In the United States, the majority of cases of MIS-C have been reported from New York. The New York State Department of Health has reported 202 cases of MIS-C with 3 deaths from late April 2020 through June 6, 2020.

 Blacks are overrepresented, accounting for 31% of the cases compared with 22% for white cases, 17% other, 26% unknown, and 3% Asian. The median age of these children is about 9 years.

Whereas MIS-C patients may present with one or more features reminiscent of KD, there are many other, often strikingly different features of the 2 conditions, supporting the concept that they are fundamentally different illnesses (Table). The study from Italy

 by definition selected children with KD-like features, yet many differences in these cases from classic KD are apparent.

There are markedly different demographic features in these 2 conditions, with very distinctive age and racial distributions. Whereas the median age of KD children is 2 years and 80% are aged younger than 5 years, MIS-C patients are much older with a median age of 10 to 11 years in most series and include many adolescents, teenagers, and even a few young adults. Additionally, the attack rates for KD are very much higher among Japanese, Korean, and Chinese children compared with other racial groups whereas Asian populations have been very underrepresented in MIS-C reports to date despite marked SARS-2 exposures. Several of the series of MIS-C patients strongly suggest overrepresentation of children of African backgrounds.

Although some of the dermatologic and mucosal features of KD may be present, MIS-C patients typically present with much more severe abdominal complaints of pain with diarrhea and/or vomiting compared with KD patients, as well as manifesting multiorgan system involvement and cardiogenic shock. A small (approximately 2%) subset of KD patients can develop KDSS but they often have significant coronary abnormalities as well. The latter patients are somewhat clinically similar to those with TSS.

Additionally, the hallmark of KD is the development of coronary artery abnormalities, whereas evidence of significant myocardial involvement is mainly limited to the small group of KDSS patients. In striking contrast, MIS-C patients typically present with shock and with moderate-to-severe myocardial dysfunction with low LVEFs, and only a relative handful have had coronary abnormalities, often mild and of unclear significance.

By definition, MIS-C patients have evidence of recent SARS-CoV-2 infection, while KD patients do not. Some of the laboratory features of MIS-C strongly resemble those of MAS such as elevated ferritin, D-dimers, triglycerides, and some are indicative of myocardial dysfunction such as elevated troponin and very elevated NT-proBNP-levels in the greater-than-30,000 pg/mL range. In addition, MIS-C patients typically have lymphopenia, neutrophilia, thrombocytopenia, and very high CRP levels on presentation, unlike KD patients who rarely share these abnormalities and have more modestly elevated CRP levels.

Overall, the picture of MIS-C in many respects closely resembles the later phase seen in many adult COVID-19 patients of “cytokine storm,” with hyperinflammation, multiorgan damage including kidney and myocardium, with features of MAS and TSS. It is not at all clear why MIS-C patients have almost always had no early COVID-19 manifestations and that their illnesses typically present 4 to 6 weeks after the peak COVID-19 activity in a region. In this regard, MISC can be considered a postinfectious illness. Of great interest is the fact that MIS-C patients typically respond very well to IVIG with or without IV steroid, probably by effectively modulating cytokine activation. The role of additional therapies including anticoagulation with low-dose molecular heparin, aspirin, or the IL-1 inhibitor anikinra remains speculative at present.

In summary, the newly described MIS-C is quite distinct from KD. It is likely a postinfectious inflammatory syndrome as evidenced by the delay in onset from the peak of COVID cases, by the time from the apparent exposure to SARS-CoV-2 to onset of symptoms in many of the reported cases, and by the very marked elevations in inflammatory and myocardial markers observed in these cases. Thus MIS-C may be analogous to the later phase of adult COVID-19 that is also characterized by cytokine storm that may include severe myocardial dysfunction, acute kidney injury, and laboratory markers of MAS.

World Health Organization (WHO). Coronavirus disease (COVID-19). Situation report—138. Available at: 

https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200606-covid-19-sitrep-138.pdf?sfvrsn=c8abfb17_4

Published June 6, 2020. Accessed June 12, 2020.

Centers for Disease Control and Prevention (CDC). Coronavirus disease 2019 (COVID-19). Cases in the US. Available at: (

www.cdc.gov/coronavirus/2019-ncov/cases-updates/cases-in-us.html

. Updated June 11, 2020. Accessed June 12, 2020.

Centers for Disease Control and Prevention (CDC). Multisystem inflammatory syndrome (MIS-C). Information for healthcare providers about multisystem inflammatory syndrome in children (MIS-C). Case definition for MIS-C. Available at: 

. Reviewed May 29. 2020. Accessed June 12, 2020.

Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. 

. May 7, 2020. Epub ahead of print. doi: 10.1016/S0140-6736(20)31094-1

Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. 

. May 13, 2020. Epub ahead of print. doi: 10.1016/S0140-6736(20)31103-X

Belhadjer Z, Méot M, Bajolle F, et al. Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic

. May 17, 2020. Epub ahead of print. doi: 10.1161/CIRCULATIONAHA.120.048360

Toubiana J, Poirault C, Corsia A, et al. Kawasaki-like multisystem inflammatory syndrome in children during the COVID-19 pandemic in Paris, France: prospective observational study. 

New York State. Novel coronavirus. Childhood inflammatory disease related to COVID-19. Available at: 

https://coronavirus.health.ny.gov/childhood-inflammatory-disease-related-covid-19

 Updated June 12, 2020. Accessed June 12, 2020.

Children who at first did not appear to contract COVID-19 have been found to exhibit a more serious illness that has now been reported worldwide. Two experts offer guidance on recognizing and treating multisystem inflammatory syndrome in children (MIS-C).

Multisystem inflammatory syndrome in children associated with COVID-19

A 16-year-old girl presents for evaluation of a rash on her left forearm (Figure). Two days earlier, she was volunteering in the community, cleaning up a park by clearing plants and placing them in recycling bags, when she experienced sudden onset of a burning sensation on her left forearm associated with 2 enlarging red areas that became increasingly pruritic and edematous. The following day, she developed black macules on her forearm that she was unable to wash off.

Diagnosis: Urushiol dermatitis/”Black-spot” poison ivy

Allergic contact dermatitis as a result of poison ivy, poison oak, and poison sumac is an exceedingly common cause of Type IV hypersensitivity reaction. It results from allergens contained in urushiol, the resinous sap found in the stems, roots, and leaves of plants belonging to the genus 

 This reaction is characterized by a pruritic, erythematous rash, with papules and vesicles often in a linear distribution.

“Black-spot” poison ivy is an uncommon presentation of this common reaction, and as such may cause diagnostic confusion and alarm. Black enamel-like deposits are often seen on the surface of the plants themselves in areas of trauma, and this can be used in the field to identify plants from the genus 

. Leaves crushed between sheets of white paper cause the paper to turn dark brown within minutes and black by 24 hours as a result of oxidation of the urushiol.

 It is thought that this reaction occurs due to oxidation of concentrated urushiol under certain conditions, and it is reproducible on application of this substance to the skin, initially with black discoloration and after several days developing a lacquer-like appearance. These spots are adherent and cannot be removed.

Interestingly, the resin has the potential to cause dermatitis indefinitely

 and cannot be removed from clothing by washing.

 Histologically, biopsied specimens demonstrate the resin on the surface of the stratum corneum with a neutrophilic infiltrate and areas of epidermal necrosis beneath it (in contrast to the typical presentation of poison-ivy dermatitis without black discoloration, in which biopsy reveals superficial perivascular infiltration with no evidence of resin and no associated necrosis). This suggests both an irritant and allergic contact dermatitis.

There have been several case series of such “black-spot” poison ivy dermatitis,

 with patients often initially presenting concerned about more serious pathology, including melanoma. Treatment mirrors that as for classic contact dermatitis and includes topical steroids and oral antihistamines with the addition of oral steroids only as needed in extensive cases or those that involve the face or groin.

The patient was advised of the diagnosis and treated with triamcinolone 0.1% topical ointment, with topical mupirocin for any open areas. The following day, after a swim meet, she re-presented to the emergency department with new red raised eruptions around her eyes and neck, likely from contact with her arm or a delayed eruption from the original contact. She was treated with oral prednisone and did not require further follow-up.

Kim Y, Flamm A, ElSohly MA, et al. Poison ivy, oak, and sumac dermatitis: What is known and what is new?. 

Guin JD. The black spot test for recognizing poison ivy and related species. 

Mallory SB, Miller OF 3dU, Tyler WB. Toxicodendron radicans dermatitis with black lacquer deposit on the skin. 

Goldstein N. The ubiquitous urushiols contact dermatitis from mango, poison ivy, and other "poison" plants. 1968. 

Kurlan JG, Lucky AW. Black spot poison ivy: a report of 5 cases and a review of the literature. 

Hurwitz RM, Rivera HP, Guin JD. Black-spot poison ivy dermatitis. An acute irritant contact dermatitis superimposed upon an allergic contact dermatitis. 

A 16-year-old girl presents for evaluation of a rash on her left forearm, which was 2 enlarging red areas that became increasingly pruritic and edematous. What's the diagnosis?

Itchy black spots: Poison ivy or something else?

Humans do not have any natural immunity to COVID-19. We do not have an effective antiviral medication for nonhospitalized patients. We do not have a vaccine and may not for at least a year. Perhaps we should optimize the human body’s natural response to infections. To us, that means helping fever do its job.

When the body is invaded by a new germ, it mounts a fever. The fever ramps up our immune system, which is necessary to fight infections.

 All warm-blooded animals get fevers when they have infections. Every aspect of our immune system works better at a higher temperature. Was that a design flaw? Why would our bodies waste energy on something that isn’t helpful?

Dogs, rabbits, mice, ferrets, lizards, fish, and other species have been studied for what happens if we inject them with germs and suppress their fever. They have a higher death rate.

 Humans should be no different. Yet you ask: Are there similar studies on humans?

Research has shown that people with infections who are treated with fever-reducing medicines have symptoms that often are more severe and last longer than those who don’t take antifever medicines.

 These articles on rhinovirus, influenza, chickenpox, and other respiratory infections all showed improved outcomes if the associated fever was not treated. To date, there is no published research that shows treating fevers with antipyretics improves outcomes.

What about fever from vaccines? Two studies looked at what happens if we give prophylactic antipyretics to young children before or immediately after vaccines.

 Both found that antipyretics cause a lower antibody response when measured one month later.

Obviously, our views apply to all viral infections, not just the dangerous one that currently holds center stage. We would suggest health care professionals stop interfering with the human body’s attempt to cure itself. Here’s how we might do that:

Understand that the human body has a thermostat in the hypothalamus that keeps the fever in the optimal range for fighting infections.

Do not treat all fevers with antipyretics (acetaminophen or ibuprofen).

Never treat with combination (dual) antipyretics. It’s one of the main causes of fever phobia, mainly propagated by physicians and nurses.

Keep patients well hydrated so they can easily give off heat by sweating if they need to.

Teach the public that most fevers are good, not bad. Teach that reducing fevers may make you feel better but delay your recovery.

Teach the public that every time we give an antipyretic, we dampen the body’s natural immune response. That’s why the fever always returns when the medicine wears off.

In summary, there is evidence that fever improves outcomes for infections. Of note, there is no evidence to the contrary. Let’s be evidence based.

The human body wants to recover, to survive. Shouldn’t we support that?

Evans SS, Repasky EA, Fisher DT. Fever and the thermal regulation of immunity: The immune system feels the heat. 

Kluger MJ, Ringler DH, Anver MR. Fever and survival. 

Bernheim HA, Kluger MJ. Fever: effect of drug-induced antipyresis on survival. 

Rodbard D. The role of regional body temperature in the pathogenesis of disease. 

Stanley ED, Jackson GG, Panusarn C, Rubenis M, Dirda V. Increased virus shedding with aspirin treatment of rhinovirus infection. 

Doran TF, De Angelis C, Baumgardner RA, Mellits ED. Acetaminophen: more harm than good for chickenpox? 

Graham NM, Burrell CJ, Douglas RM, Debelle P, Davies L. Adverse effects of aspirin, acetaminophen, and ibuprofen on immune function, viral shedding, and clinical status in rhinovirus-infected volunteers. 

Sugimura T, Fujimoto T, Motoyama H, et al. Risks of antipyretics in young children with fever due to infectious disease. 

Schulman CI, Namias N, Doherty J, et al. The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. 

Prymula R, Siegrist CA, Chilbek R, et al. Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials. 

Li-Kim-Moy J, Wood N, Jones C, Macartney K, Booy R. Impact of fever and antipyretic use on influenza vaccine immune responses in children. 

Most fevers are good, not bad. Here’s why pediatricians should respect fever.

Could fever improve COVID-19 outcomes?

A limited abdominal ultrasound (US) is a safe and e­ffective way to assess for intestinal malrotation (IM) with or without midgut volvulus (MGV), according to a retrospective study. An upper gastrointestinal (UGI) series has long been considered the imaging gold standard for making this assessment.

Investigators searched radiology reports at a children’s hospital for patients who were evaluated for MGV using US during 2016 and 2017 and examined the relevant charts for any events that happened in the month following the US. Of the 195 patients who received a US evaluation, the most common presentations were vomiting (44%) followed by abdominal pain and suspected malrotation. Median age was 77 days, with 91% of patients aged younger than 1 year, half of whom were aged younger than 1 month.

The US studies were evaluated for 2 abnormalities: twisting of the small bowel and vasculature around the superior mesenteric artery (SMA), indicative of IM; and occlusion of the SMA, indicating MGV. Of the 195 US studies, 179 were diagnostic; that is, they could include or exclude MGV. (Sixteen studies were not diagnostic because of overlying bowel gas.) Of the diagnostic studies, 14 were found to be positive for MGV, which was confirmed at surgery. For the 164 patients with a negative US who did not have surgery, no negative outcomes were reported. In other words, US was diagnostic in 92% of patients, and in those individuals, it had a sensitivity and specificity of 100%.

Seven of the 16 patients with nondiagnostic US studies were evaluated further with UGI exams, and all tested negative for MGV or malrotation, although 1 patient later was confirmed surgically to have malrotation without volvulus. The remaining 6 patients did not receive further imaging, and either were followed clinically (their symptoms resolved) or underwent surgical exploration that revealed other causes of abdominal pain.

The authors noted that unlike UGI, US does not expose the child to radiation or fill his or her stomach with contrast. In addition, US offers portability and repeatability (

. 2020;S0022- 3468(20)30295-5. Online ahead of print.

Anything that can be done noninvasively at the bedside is a tremendous boon, both in terms of minimizing risk and getting a child to the operating room sooner when needed. The ultrasound is taking on more of the functions of a Star Trek tricorder every day.

A retrospective study examines whether limited abdominal ultrasound is a safe and e­ffective way to assess for intestinal malrotation with or without midgut volvulus.

Ultrasound accurately diagnoses midgut volvulus

A recent case report describes how appendicitis in a 9-year-old child with sickle cell disease was handled effectively with nonsurgical treatment.

The child, who has sickle beta zero thalassemia and moderate persistent asthma, visited an emergency department because of lower back, chest, and abdominal pain that had not responded to ibuprofen. Doctors diagnosed vasoocclusive crisis, and the child was given intravenous fluids and analgesia. Abdominal ultrasound did not visualize the appendix, and results of abdominal computerized tomography were consistent with acute appendicitis without perforation.

Considered a high surgical risk, the child was given medical therapy, including ciprofloxacin and metronidazole, and after a day of not eating was transitioned to a full liquid diet. By the fifth day of hospitalization his respiration had improved significantly, and he was discharged on day 6. A year later, his abdominal pain had not returned (

Although rarely discussed in pediatric literature, using medical therapy with early introduction of antibiotics for acute appendicitis is not a new concept. Given how easily and relatively risk free appendectomy is to perform (especially laparoscopically), surgery is still the standard of care. However, keep an open mind about medical treatment if a surgeon believes that operating might be the greater risk.

A case report examines whether a high-risk child with appendicitis will need surgery.

Appendectomy successfully averted in child considered at high surgical risk

A study in postmenarchal youngsters aged from 8 to 19 years found that the levonorgestrel intrauterine device (IUD) is successful in controlling abnormal uterine bleeding and in suppressing menses.

Investigators reviewed the charts of 166 patients who had the devices inserted at some point during a 6-year period for whom follow-up data (from 3 to 60 months after insertion) were available. Some of these patients used the 52-mg IUD and others the 13.5-mg IUD. The IUDs were inserted for contraception, management of heavy menstrual bleeding, and menstrual suppression. Researchers collected data on menstrual history and demographics before and after the devices were inserted.

The overall rate of amenorrhea among participants was 39.8%, with no difference between the patients having the 52-mg IUD and those with the 13.5-mg device. Preinsertion menstrual characteristics, such as regularity and flow of the menstrual cycle or a history of bleeding or of developmental delay, did not have a significant effect on the rate of amenorrhea or bleeding patterns after insertion.

Of the 100 patients who did not experience amenorrhea, 32% reported light vaginal bleeding and 35% reported moderate or heavy vaginal bleeding. Among users who described their cycle as regular before insertion, 28.6% reported spotting, 26.8% said they had light vaginal bleeding, and 44.6% had moderate to heavy bleeding after insertion. These proportions were not significantly different among those who described their cycle as irregular before IUD insertion, although only 23.3% in this group reported moderate to heavy vaginal bleeding later. Complications were rare; no uterine perforations were reported; and only 5.4% expelled the IUD (

. 2020; S1083-3188(20)30223-0. Online ahead of print.

Intrauterine devices have been demonstrated to be safe and effective with results comparable to, or better than, hormone therapy. They are underutilized in teenagers but should be considered an option. If you are uncomfortable placing the device yourself, refer the patient to a gynecologist.

A study finds that the levonorgestrel intrauterine device (IUD) is successful in controlling abnormal uterine bleeding and in suppressing menses in teenagers.

Vol 37 No 7