Many children get mild COVID-19 symptoms but with hight chance of transmission to adults

0
483

A new Chinese study of coronavirus infection in kids could bring comfort to American parents—and highlight the wisdom of at least temporarily closing schools.

That’s because the study, published March 13 in Nature Medicine, found that even though children typically only exhibit mild symptoms if infected, they can shed the coronavirus long after symptoms disappear.

Across the United States, local school districts have been temporarily suspending classroom activity, instead opting for online, at-home instruction.

The new study finds “it may make sense to close schools, since it’s unclear if children might be able to pass it to others in the community,” said Dr. Robert Glatter. He is an emergency medicine physician at Lenox Hill Hospital in New York City.

In the study, a team led by Huimin Xia, of Guangzhou Women and Children’s Medical Center, in Guangzhou, China, outlined a study of 745 Chinese babies and children.

The kids ranged in age from 2 months to 15 years, and all had experienced “close contact with diagnosed [COVID-19] patients or were members of families with reported familial outbreaks,” according to a journal news release.

The good news: just 10 children (1.3%) ended up testing positive for the new coronavirus, Xia’s team reported.

All were admitted to a treatment center-not because they were overly sick, but because testing of families affected by coronavirus had brought their infection to light.

Even better news: None of the 10 kids developed severe symptoms. Seven developed a fever, but none of the fevers exceeded 39 degrees Celsius (102.2 Fahrenheit).

“There were some instances of coughing, sore throat and nasal congestion,” the journal news release noted, but “none of the other symptoms commonly seen in adult patients, such as muscle ache and headache.” Chest X-rays showed no signs of pneumonia in any of the children.

But there was also a downside to these milder symptoms: Many children might be asymptomatic or minimally symptomatic vectors of transmission for the coronavirus as they come into contact with more vulnerable adults.

And that risk of transmission may occur over a longer time than was suspected, the Chinese team noted.

That’s because even after swabs of the previously infected children’s noses and throats came up negative for coronavirus, tests of their stool continue to show signs of the virus.

In one case, a child had a stool test that still tested positive for coronavirus 13 days after they had been discharged from hospital following two negative throat/nose swab tests.

And that might have implications for precautions such as length of quarantine, Xia’s team noted.

Quarantine timings are currently assessed through the use of nose or throat swabs; however, these results suggest that gastrointestinal-tract testing may help to provide more accurate assessments of treatment effectiveness and recovery,” according to the journal news release.

Glatter agreed, but said more research needs to be done.

“It’s important to understand that viral shedding [in stool samples] seen in this small study does not equate with transmission,” he said.

“While children may still shed virus in their stool, we don’t know whether they may still be infectious and serve as a reservoir of ongoing transmission.”

Still, “the report suggests that rectal swab testing may be a more sensitive indicator compared to nasal sampling regarding effectiveness of treatment and when to end quarantine,” Glatter added.


CLINICAL

  • COVID-19 is the disease, SARS-CoV-2 is the virus.
  • Epidemiology
    • China remains with most reported cases, but as of March 2020, the upswing in many countries including especially S. Korea, Italy, France, US
      • COVID-19 cases reported in many countries and all continents except Antarctica.
    • Real-time global reports available through Coronavirus COVID-19 Global Cases Dashboard by Johns Hopkins CSSE
    • Average age appears to be in the mid- to late 50s with slight male predisposition among early series from Wuhan City.
    • Children appear less symptomatic with infection and less prone to severe illness.
  • Transmission
    • By respiratory droplets and by fomite. Virus found in respiratory secretions and saliva.
    • Stool shedding also described, but uncertain what role, if any, that plays.
  • Incubation period
    • Mean of 6.4 days, range 2-12. For people quarantined, 14d observation recommended to exclude infection, though 24d asymptomatic time from exposure described.
    • Viral shedding occurs following recovery, but unclear what role this plays in transmission.
    • Children and intrafamilial spread appear to be a growing means of transmission.
  • Disease spectrum
    • ~80% of infections are not severe and some may be asymptomatic.
    • Illnesses caused by the virus are primarily upper respiratory tract infections and pneumonia.
    • For hospitalized patients with pneumonia, limited studies suggest the disease course (Wuhan experience):
      • ~50% develop hypoxemia by day 8
      • ARDS develops in 17-29%
      • Patients in the ICU require:
        • Non-invasive ventilation (42%)
        • Mechanical ventilation (47%)
        • High-flow O2 (11%)
        • ECMO (2-5%)
  • Symptoms
    • Fever (83-98%)
    • Cough (46-82%, usually dry)
    • Shortness of breath at onset (31%)
    • Myalgia or fatigue (11-44%)
    • Less common symptoms:
      • Pharyngitis
      • Headache
      • Productive cough
      • GI symptoms
      • Hemoptysis
  • Differential diagnosis
  • COVID-19 testing
    • With limited testing capacities in many locations, clinicians should use their judgment to determine if a patient has signs and symptoms compatible with COVID-19 and whether the patient should be tested.
    • Priority should be given for those groups below.
    • The most common symptoms include fever (subjective or confirmed), cough (usually dry) and shortness of breath.

Mortality

  • Note that early data is from China, there appears to be great variability among countries.
  • The mortality rate is thought to be ≤2%, but precise numbers uncertain due to a lack of available serological testing.
  • The mortality rate is less than that commonly ascribed to severe community-acquired pneumonia (12-15%) but more than seasonal influenza (~0.1%).
  • Most deaths in patients with comorbidities and often elderly (> 60 considered a “risk factor”), although healthy younger patients also described.

SITES OF INFECTION

  • Pulmonary
  • GI
    • Some patients have nausea, vomiting or diarrhea.
    • The virus has been recovered from stool, but the significance is uncertain.

TREATMENT

General

  • Supportive care, including oxygen, mechanical ventilation if needed.
  • If epidemic widespread, public health officials may recommend those with minor symptoms to stay home and not seek care in health clinics or hospitals.
    • Limit medical care to those who are short of breath, have severe symptoms or who require oxygen and supportive care that is only available in a hospital.

Antivirals and immunomodulators

  • No proven efficacy in humans as of March 14, 2020.
    • Chinese Guidelines for COVID-19 suggest using chloroquine, traditional Chinese medicines, and for anti-IL6R drug tocilizumab as an anti-inflammatory in patients with extensive lung disease/severe illness and elevated IL-6 levels.
  • A large number of antivirals and immunomodulators are being investigated.
    • Caution is advised as to whether any are effective or safe for COVID-19.
    • Types of drugs under investigation include antivirals (protease inhibitors, influenza drugs, nucleoside analogs) anti-inflammatories, surface protein antagonists such as lecithins.
    • Much like with influenza, antiviral drugs are likely to be most effective as a preventative or with administration early after the onset of symptoms.
  • Drugs currently under investigation[16]:
    • Remdesivir (Gilead; used to treat Ebola)
      • Currently under study in a trial in Wuhan; activity is seen in vitro with SARS-2-CoV, MERS-CoV (also including MERS-CoV primate studies).
      • Likely the most promising drug.
    • Chloroquine (or hydroxychloroquine) has been reported to have some efficacy in vivo and in COVID-19 pneumonia, the mechanism may be by interfering with cellular acidification in the phagolysosome.[8],[9]
    • ASC09/ritonavir, lopinavir/ritonavir, with or without umifenovir
    • ASC09/oseltamivir, ritonavir/oseltamivir, oseltamivir
    • Azvudine
    • Baloxavir marboxil/favipiravir and lopinavir/ritonavir in combination(s)
    • Camostat mesylate
    • Darunavir/cobicistat alone or with lopinavir/ritonavir and thymosin α1 in combination(s)
    • Interferon alfa-2b alone or in combination with lopinavir/ritonavir and ribavirin
    • Methylprednisolone
    • Camrelizumab and thymosin
    • Tocilizumab

Prevention

  • No vaccine is currently available.
  • As a newly described virus, much remains to be learned.
    • Travel restrictions, quarantines, school closings, mass social distancing of uncertain long-term benefits with this viral infection and remain a source of considerable debate about effectiveness and costs among public health officials and politicians[3].
    • Difficulty sorting other causes of respiratory illness from the novel coronavirus, especially during influenza season.
  • Healthcare workers and health systems in the U.S.
    • Recommend following CDC Guidance for Risk Assessment and Public Health Management of SARS-CoV-2 (2019-nCoV).[17]
    • Likely that standard contact and respiratory droplet precautions are sufficient (as with SARS, MERS) which is the WHO recommendation; however, some debate using negative pressure rooms for extra safety but then this may divert from known needs such as TB or measles.
      • Current CDC recommendations are for aerosol (e.g., use of negative pressure isolation), but if resources strained, then pivot to droplet and standard precautions.
  • General measures recommended:
    • Avoid sick individuals.
    • Wash hands with soap and water x 20 seconds before eating, after cough/sneezing or bathroom visits.
    • Don’t touch the face, eyes, etc.
    • Stay home if ill.
    • Cover your sneeze.
    • Disinfect frequently touched household objects.
    • Current CDC recommendations do not suggest using a facemask for protection.

FOLLOW UP

  • Early Wuhan experience suggested a case fatality rate as high as 4.3%, but likely 2% elsewhere in China.
  • Preliminary evidence suggests two strains of SARS-2-CoV circulating: one associated with milder illness (~30%), the other with severe illness (70%).
  • Case fatality rates in other countries (as of March 2020) appear lower, but are higher in elderly, sick populations (e.g., Evergreen Health, Seattle, WA; Northern Italy).

OTHER INFORMATION

  • Recommendations to consider testing for all respiratory symptomatic patients will be limited by the availability of SARS-CoV-2 testing.
  • Severe illness is likely to strike the same populations at high risk for complications of seasonal influenza (e.g., elderly, immunosuppressed, and with comorbidities).
  • The case fatality rate is probably higher than seasonal influenza (≤0.1%) but lower than initially reported (~ 2-4%).
    • Current estimates suggest COVID-19 is ~10x worse than seasonal influenza.
    • Serological testing of larger populations will give a clearer picture of infectious impact.

References

  1. Al-Tawfiq JA, Al-Homoud AH, Memish ZA. Remdesivir as a possible therapeutic option for the COVID-19. Travel Med Infect Dis. 2020.  [PMID:32145386]Comment: This parenteral agent appears to be the most promising agent from in vitro and animal data (from MERS-CoV). We await RCT information from China, hopefully, available in April 2020.
  2. Colson P, Rolain JM, Lagier JC, et al. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents. 2020.  [PMID:32145363]Comment: Raoult knows these drugs well from Q fever and Whipple’s disease studies. Caution though is that preliminary in vitro data rarely translates into effectiveness in human infection, hence a plea to only trial drugs within an RCT. How this drug may work is alkalinizing the phagolysosome within cells and may have had some effectiveness in SARS. Early study in China of the in vitro activity of chloroquine against SARS-CoV-2, discovered during culture tests on Vero E6 cells with 50% and 90% effective concentrations (EC50 and EC90 values) of 1.13 μM and 6.90 μM, respectively (antiviral activity being observed when addition of this drug was carried out before or after viral infection of the cells)
  3. Chinazzi M, Davis JT, Ajelli M, et al. The effect of travel restrictions on the spread of the 2019 novel coronavirus (COVID-19) outbreak. Science. 2020.  [PMID:32144116]Comment: Although extraordinary measures may have slowed or stopped COVID-19 in China, questions remain whether this is durable and at what cost to society? It may buy time but effective drugs or vaccines remain in the far future it seems. Authors suggest “the travel quarantine of Wuhan delayed the overall epidemic progression by only 3 to 5 days in Mainland China, but has a more marked effect at the international scale, where case importations were reduced by nearly 80% until mid-February. Modeling results also indicate that sustained 90% travel restrictions to and from Mainland China only modestly affect the epidemic trajectory unless combined with a 50% or higher reduction of transmission in the community.”
  4. Mizumoto K, Chowell G. Estimating Risk for Death from 2019 Novel Coronavirus Disease, China, January-February 2020. Emerg Infect Dis. 2020;26(6).  [PMID:32168464]Comment: An early report and these typically have higher rates of infection due to concentrated, very ill patients than later in epidemics. Authors estimate of the risk for death in Wuhan reached values as high as 12% in the epicenter of the epidemic and ≈1% in other, more mildly affected areas. The elevated death risk estimates are probably associated with a breakdown of the healthcare system.
  5. Liu W, Zhang Q, Chen J, et al. Detection of Covid-19 in Children in Early January 2020 in Wuhan, China. N Engl J Med. 2020.  [PMID:32163697]Comment: A retrospective look at 366 children hospitalized for respiratory illness. SARS-CoV-2 detected only in 6 (1.6) of patients. Only 1 of the COVID children required ICU care. Of the COVID patients, fever and cough were common and four had pneumonia.
  6. Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020.  [PMID:31978945]Comment: An early report includes electron microscopy photomicrographs as well as sequence analysis of what is now termed COVID-19 disease and SARS-2-CoV virus.
  7. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020.  [PMID:32015507]Comment: Authors have sequenced what is now termed SARS-2-CoV. Its genome 79.5% sequence identify to SARS-CoV. Furthermore, it was found that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus.
  8. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020.  [PMID:32074550]Comment: An early report that suggests the antimalarial chloroquine has shown efficacy against COVID-19 infection in Chinese trials. Of note, this drug has been tried for CHKV and others without good virological effect.
  9. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020.  [PMID:32020029]Comment: Summary of earlier in vitro studies suggesting drugs that may work against COVID-19. Remdesivir is currently under investigation in the Wuhan epidemic. This drug has also shown activity in a rhesus macque module of MERS-CoV.
  10. Bajema KL, Oster AM, McGovern OL, et al. Persons Evaluated for 2019 Novel Coronavirus – United States, January 2020. MMWR Morb Mortal Wkly Rep. 2020;69(6):166-170.  [PMID:32053579]Comment: People evaluated as per this report in the US mostly were those with a history of travel/contacts from Wuhan City, China which is the apparent epicenter of this epidemic. Of 210 people, 148 (70%) had travel-related risk only, 42 (20%) had close contact with an ill laboratory-confirmed 2019-nCoV patient or PUI, and 18 (9%) had both travel- and contact-related risks. Eleven of these persons had a laboratory-confirmed 2019-nCoV infection. Given reports now around the globe, it is unclear if testing only those with potential links to China is prudent, but the current availability of test kits from the CDC likely precludes wider testing until either FDA-approved or EUA approval is given to current commercially available respiratory panels to include COVID-19.
  11. Benvenuto D, Giovanetti M, Salemi M, et al. The global spread of 2019-nCoV: a molecular evolutionary analysis. Pathog Glob Health. 2020.  [PMID:32048560]Comment: Strain analysis to date of COVID-19 suggests that they are very similar to bat SAR-like coronavirus.
  12. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020.  [PMID:32031570]Comment: One of the initial major reports of the Wuhan COVID-19 epidemic. In this series, the median age was 56 and slightly more men (54%) affected. Predominant symptoms include fever, fatigue and dry cough. Leukopenia was seen in ~70%. Thirty-six patients (26.1%) were transferred to the intensive care unit (ICU) because of complications, including acute respiratory distress syndrome (22 [61.1%]), arrhythmia (16 [44.4%]), and shock (11 [30.6%]).
  13. Ai T, Yang Z, Hou H, et al. Correlation of Chest CT and RT-PCR Testing in Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology. 2020.  [PMID:32101510]Comment: Chest CT shows early ground-glass infiltrates which may offer speedier “diagnosis” than PCR studies in an epidemic setting as a first finding if molecular assays not readily available.
  14. Kam KQ, Yung CF, Cui L, et al. A Well Infant with Coronavirus Disease 2019 (COVID-19) with High Viral Load. Clin Infect Dis. 2020.  [PMID:32112082]Comment: No surprise, here an infant sheds high levels of the virus but is without symptoms. Children are well known “vectors” of viral infection often without significant disease is well known for regular coronavirus infections, influenza and others.
  15. Interim Infection Prevention and Control Recommendations for Patients with Confirmed Coronavirus Disease 2019 (COVID-19) or Persons Under Investigation for COVID-19 in Healthcare Settings. U.S. Centers for Disease Control and Prevention. [https://www.cdc.gov…]
  16. Harrison, C. Coronavirus puts drug repurposing on the fast track. Nature Feb 27, 2020 (https://www.nature.com/articles/d41587-020-00003-1 , accessed 3/3/20)Comment: A look at the clinicaltrials.gov and Chinese clinical trial web sites that have registered trials.
  17. Interim U.S. Guidance for Risk Assessment and Public Health Management of Healthcare Personnel with Potential Exposure in a Healthcare Setting to Patients with Coronavirus Disease 2019 (COVID-19). U.S. Centers for Disease Control and Prevention. [https://www.cdc.gov…


More information: Yi Xu et al. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding, Nature Medicine (2020). DOI: 10.1038/s41591-020-0817-4

LEAVE A REPLY

Please enter your comment!
Please enter your name here

Questo sito usa Akismet per ridurre lo spam. Scopri come i tuoi dati vengono elaborati.