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. 2021 Sep 2;73(Suppl_3):S218-S228.
doi: 10.1093/cid/ciab509.

Deaths Attributed to Respiratory Syncytial Virus in Young Children in High-Mortality Rate Settings: Report from Child Health and Mortality Prevention Surveillance (CHAMPS)

Dianna M Blau  1 , Vicky L Baillie  2 , Toyah Els  2 , Sana Mahtab  2 , Portia Mutevedzi  2 , Adama Mamby Keita  3 , Karen L Kotloff  4 , Ashka Mehta  4 , Samba O Sow  3 , Milagritos D Tapia  4 , Beth A Tippett Barr  5 , Benard O Oluoch  6 , Clayton Onyango  5 , Gunturu Revathi  7 , Jennifer R Verani  8 , Mahlet Abayneh  9 , Nega Assefa  10 , Lola Madrid  10   11 , Joseph O Oundo  11 , J Anthony G Scott  11 , Quique Bassat  12   13   14   15   16 , Inacio Mandomando  13   17 , Antonio Sitoe  13 , Marta Valente  12 , Rosauro Varo  12   13 , Ima-Abasi Bassey  18 , Carrie Jo Cain  19 , Amara Jambai  20 , Ikechukwu Ogbuanu  21 , Julius Ojulong  18 , Muntasir Alam  22 , Shams El Arifeen  22 , Emily S Gurley  22   23 , Afruna Rahman  22 , Mustafizur Rahman  22 , Jessica L Waller  24 , Betsy Dewey  25 , Robert F Breiman  25 , Cynthia G Whitney  25 , Shabir A Madhi  2 ; CHAMPS Consortium
Collaborators, Affiliations

Deaths Attributed to Respiratory Syncytial Virus in Young Children in High-Mortality Rate Settings: Report from Child Health and Mortality Prevention Surveillance (CHAMPS)

Dianna M Blau et al. Clin Infect Dis. .

Abstract

Background: Lower respiratory tract infections are a leading cause of death in young children, but few studies have collected the specimens needed to define the role of specific causes. The Child Health and Mortality Prevention Surveillance (CHAMPS) platform aims to investigate causes of death in children aged <5 years in high-mortality rate settings, using postmortem minimally invasive tissue sampling and other advanced diagnostic techniques. We examined findings for deaths identified in CHAMPS sites in 7 countries in sub-Saharan Africa and south Asia to evaluate the role of respiratory syncytial virus (RSV).

Methods: We included deaths that occurred between December 2016 and December 2019. Panels determined causes of deaths by reviewing all available data including pathological results from minimally invasive tissue sampling, polymerase chain reaction screening for multiple infectious pathogens in lung tissue, nasopharyngeal swab, blood, and cerebrospinal fluid samples, clinical information from medical records, and verbal autopsies.

Results: We evaluated 1213 deaths, including 695 in neonates (aged <28 days), 283 in infants (28 days to <12 months), and 235 in children (12-59 months). RSV was detected in postmortem specimens in 67 of 1213 deaths (5.5%); in 24 deaths (2.0% of total), RSV was determined to be a cause of death, and it contributed to 5 other deaths. Younger infants (28 days to <6 months of age) accounted for half of all deaths attributed to RSV; 6.5% of all deaths in younger infants were attributed to RSV. RSV was the underlying and only cause in 4 deaths; the remainder (n = 20) had a median of 2 (range, 1-5) other conditions in the causal chain. Birth defects (n = 8) and infections with other pathogens (n = 17) were common comorbid conditions.

Conclusions: RSV is an important cause of child deaths, particularly in young infants. These findings add to the substantial body of literature calling for better treatment and prevention options for RSV in high-mortality rate settings.

Keywords: Respiratory syncytial virus; cause of death; child mortality.

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Figures

Figure 1.
Figure 1.
Flowchart of enrollment of deaths among children <5 years of age in Child Health and Mortality Prevention Surveillance (CHAMPS) sites, detection of respiratory syncytial virus (RSV) among deaths with minimally invasive tissue samples (MITS) tested for RSV, and identification of deaths determined by review panels (determination of cause of death [DeCoDe] panels) to be caused by RSV or other conditions.
Figure 2.
Figure 2.
Proportion of deaths with respiratory syncytial virus (RSV) detected and with RSV determined to be in the causal chain leading to death, by Child Health and Mortality Prevention Surveillance (CHAMPS) site.
Figure 3.
Figure 3.
A. Findings in a newborn with respiratory syncytial virus (RSV) determined to be the underlying and only cause of death. The subject was a 22-day-old girl, born in a healthcare facility at 38 weeks’ gestation (birthweight, 3400 g) to a mother who was positive for human immunodeficiency virus (HIV) and receiving treatment. The newborn was seen at a referral hospital after a week of difficulty breathing; the father refused admission, and the newborn was discharged on antibiotics. She developed a fever, was seen in the clinic, and was again referred for hospital care. She died at home that night. Postmortem testing was negative for HIV, tuberculosis, and malaria; blood and cerebrospinal fluid cultures were also negative. Polymerase chain reaction (PCR) testing identified RSV in lung tissue and a nasopharyngeal (NP) specimen; the latter also contained Klebsiella pneumoniae, Staphylococcus aureus, Moraxella catarrhalis, Haemophilus influenzae, and rhinovirus. Pathology found mild steatosis and extramedullary hematopoiesis in the liver, and interstitial pneumonitis in specimens from both lungs. Both images show lung tissue; the arrows in left image indicate multinucleated syncytial cells, and the circle in right image, positive immunohistochemical (IHC) staining in these cells. B, Findings after death caused by a chronic infected ulcer (underlying cause), with subsequent pneumonia caused by S. aureus and Streptococcus pneumoniae (morbid causes) and S. aureus sepsis (immediate cause) in a malnourished infant (part 2 contributing cause); RSV was detected but not deemed a cause of death. This subject was a 6-month-old girl born at 36 weeks’ gestation (birthweight, 3165 g). She presented with 1 day of cough, fever, lethargy, and decreased milk intake and 2 days of diarrhea. She had been receiving oral and topical medications for an occipital ulcer. At the admission examination, she was hot to the touch, hydrated, and in respiratory distress, with grunting, alar flaring, a respiratory rate of 62/min, and a pulse rate of 178 /min. She was treated with gentamicin and ampicillin but died the following day. S. aureus grew in cultures collected before death from the occipital abscess and blood. The infant’s weight and height at postmortem examination were 6.07 kg and 60 cm, respectively (weight-for-age z score, −2.18; weight-for-height z score, −1.5). Results of postmortem tests for HIV, tuberculosis, and malaria were negative. S. aureus grew in lung tissue culture. PCR testing detected S. aureus in blood and lung tissue. Lung tissue was also positive for S. pneumoniae. PCR results in an NP swab specimen were positive for RSV, H. influenzae, M. catarrhalis, S. pneumoniae, and S. aureus; a stool sample was positive for adenovirus 40/41 and Escherichia coli. Liver tissue pathology showed severe large- and small-droplet steatosis. Right and left lung specimens showed severe necrotizing bronchopneumonia (left image), with IHC staining positive for S. aureus (not shown) and S pneumoniae (red staining in right image). C, Findings after death in a child caused by HIV with wasting syndrome (underlying cause), malaria (morbid condition), and E. coli sepsis (immediate cause); severe anemia and polymicrobial pneumonia due to RSV, E. coli, and S. pneumoniae were considered contributing (part 2) causes. The child was a 21-month-old girl admitted to the hospital with a history of cough, fever, vomiting, and rash localized at her mouth, elbows, and buttocks. On examination, she appeared ill and wasted and was febrile. Antemortem diagnoses included severe anemia, severe malaria, pneumonia, and malnutrition; she died on hospital day 11. Postmortem weight and height were 6.7 kg and 82.1 cm, respectively (weight-for-age z score, −4.04; weight-for-height z score, −5.1). At postmortem examination, she appeared malnourished and pale, with healed sacral and trochanteric pressure sores and right elbow sores. HIV testing results were positive; results of testing for tuberculosis and malaria were negative, and a blood culture grew E. coli. PCR testing of blood identified E. coli and Plasmodium falciparum; lung tissues were positive for RSV, cytomegalovirus, M. catarrhalis, S. pneumoniae, Pneumocystis jirovecii, and K. pneumoniae; an NP specimen was positive for RSV, K. pneumoniae, S. pneumoniae, S. aureus, M. catarrhalis, Pseudomonas aeruginosa, and cytomegalovirus; and a stool sample was positive for E. coli, and Enterovirus. At pathological examination of the liver, extensive large- and small-droplet steatosis and sinusoidal leukocytosis were noted, and results of IHC testing were positive for malaria; bacterial bronchopneumonia and focal interstitial pneumonitis were seen in lung tissue. IHC tests in lung tissuee detected E. coli (left image) and S. pneumoniae (right image).
Figure 4.
Figure 4.
A. Number of conditions in the causal chain for deaths attributed to respiratory syncytial virus (RSV) (n = 24), by age group. B, Deaths in which RSV was detected but not determined to be in the causal pathway (n = 43).
Figure 5.
Figure 5.
Other pathogens determined to be in the causal chain leading to death. Abbreviations: CMV, cytomegalovirus; E coli, Eschericia coli; GBS, Group B streptococcus; hMPV, human metapneumovirus.
Figure 6.
Figure 6.
Causes of death determined by Child Health and Mortality Prevention Surveillance (CHAMPS) review (determination of cause of death) panels for the 67 deaths with specimens that tested positive for respiratory syncytial virus (RSV), by age group. Results are grouped by whether (1) RSV was in the causal chain of events leading to death (blue); (2) RSV contributed, but other conditions caused the death (orange); (3) infections other than RSV caused the death (gray); or (4) the death was caused by conditions that were not infectious.
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