Differential Cytokine Responses and the Clinical Severity of Adult and Pediatric Nephropathia Epidemica

Abstract

Nephropathia epidemica (NE), caused by the hantavirus infection, is endemic in Tatarstan Russia. The majority of patients are adults, with infection rarely diagnosed in children. This limited number of pediatric NE cases means there is an inadequate understanding of disease pathogenesis in this age category. Here, we have analyzed clinical and laboratory data in adults and children with NE to establish whether and how the disease severity differs between the two age groups. Serum cytokines were analyzed in samples collected from 11 children and 129 adult NE patients during an outbreak in 2019. A kidney toxicity panel was also used to analyze urine samples from these patients. Additionally, serum and urine samples were analyzed from 11 control children and 26 control adults. Analysis of clinical and laboratory data revealed that NE was milder in children than in adults. A variation in serum cytokine activation could explain the differences in clinical presentation. Cytokines associated with activation of Th1 lymphocytes were prominent in adults, while they were obscured in sera from pediatric NE patients. In addition, a prolonged activation of kidney injury markers was found in adults with NE, whilst only a short-lasting activation of these markers was observed in children with NE. These findings support previous observations of age differences in NE severity, which should be considered when diagnosing the disease in children.

Keywords: cytokine; nephropathia epidemica; pediatric.

Figure 1

The sites of orthohantavirus exposure. The green circles and names (PUUV strains Hu466, Hu475, Hu493, Hu497, Hu500, Hu505, Hu518, Hu520, Hu523, Hu546, Hu563, Hu566, Hu587, Hu599, Hu608, HU_611 and Hu614 from NE patients). The brown circles (Hu526, Hu545, Hu574, Hu 600 and Hu604 strains were closely related to PUUV strains from habitats of bank voles in the east and southeast suburbs of Kazan). The blue circles and names (Hu464, Hu549, Hu598 and HU_639 strains were closely related to PUUV strains from Mamadysh in the east of the Pre-Kama area). The red circles and names for (Hu465). The purple circles (PUUV HU_585, HU_626 and HU_627, Hu461, Hu471, Hu487, Hu488, Hu542, Hu578, Hu602, Hu603, Hu638 and Hu 624 strains).

Figure 2

Phylogenetic tree. Sequencing and phylogenetic analysis of PUUV strains from humans and rodents.

Figure 3

Clinical comparison of NE in adults and children. Duration of the symptoms 2nd fever, headache, lumbar pain and oliguria were recorded in both adult (blue) and child (red) NE patients. Serum creatine levels at the febrile and polyuric phases were also compared between adults (blue) and children (red) with NE. Data is presented as boxplotwith asterisks denoting statistical significance between adults and children as determined by Kruskal-Wallis test (p < 0.05).

Figure 4

Analysis of serum cytokine and kidney toxicity markers in adults and children diagnosed with NE in the febrile phase. The Bio-Plex (Bio-Rad, Hercules, CA, USA) multiplex magnetic bead-based antibody detection kit was used to measure (A) markers of kidney toxicity in the urine; (В) serum chemokines or (С) serum interleukins in adults (n = 129) and children (n = 11). Data are presented as Log2 fold change in comparison to non-NE control samples. Asterisks denote statistical significance determined by Kruskal-Wallis test with BH adjustment (p < 0.05). Dotted line indicates fold change of 1.

Figure 5

Analysis of serum cytokine and kidney toxicity markers in adults and children diagnosed with NE in oliguric phase. The Bio-Plex (Bio-Rad, Hercules, CA, USA) multiplex magnetic bead-based antibody detection kit was used to measure (A) markers of kidney toxicity in the urine; (В) serum chemokines or (С) serum interleukins in adults (n = 129) and children (n = 11). Data are presented as Log2 fold change in comparison to non-NE control samples. Asterisks denote statistical significance determined by Kruskal-Wallis test with BH adjustment (p < 0.05). Dotted line indicates fold change of 1.

Figure 6

Analysis of serum cytokine and kidney toxicity markers in adults and children diagnosed with NE in polyuric phase. The Bio-Plex (Bio-Rad, Hercules, CA, USA) multiplex magnetic bead-based antibody detection kit was used to measure (A) markers of kidney toxicity in the urine; (В) serum chemokines or (С) serum interleukins in adults (n = 129) and children (n = 11). Data are presented as Log2 fold change in comparison to non-NE control samples. Asterisks denote statistical significance determined by Kruskal-Wallis test with BH adjustment (p < 0.05). Dotted line indicates fold change of 1.