Posthematopoietic stem cell transplant COVID‐19 infection in a pediatric patient with IPEX syndrome

To the Editor:

December 2019 marked the emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). ⁸ , ⁹ Several treatment approaches are under study. The antiviral remdesivir ¹⁰ has been shown to improve overall mortality in patients treated for COVID‐19, ¹ and was approved by the United States Food and Drug Administration (FDA) for hospitalized patients with severe disease. ² Tocilizumab, a humanized antiinterleukin‐6 receptor ¹¹ antibody, can hasten COVID‐19‐related cytokine release syndrome recovery by 75%. ³ Implementation of COVID‐19 convalescent plasma (CCP) in the treatment of COVID‐19 infection was also suggested by the FDA. ⁴

An 8‐year‐old African‐American male with immune‐dysregulation polyendocrinopathy X‐linked (IPEX) syndrome underwent haploidentical, related bone marrow hematopoietic stem cell transplant (HSCT), and contracted SARS‐CoV‐2 during the periengraftment period, subsequently developing primary graft failure. The conditioning regimen included busulfan, fludarabine, rabbit antithymoglobulin, and posttransplant cyclophosphamide; graft versus host disease (GVHD) prophylaxis consisted of mycophenolate mofetil and cyclosporine.

Lack of engraftment and fever were noted on Day + 21 posttransplant. A sedated bone marrow aspiration was planned; prior to sedation he tested positive for COVID‐19 via nucleic acid amplification test. Development of respiratory distress prompted a chest CT that showed “bilateral ground‐glass opacities” (Figure 1); noninvasive ventilation was initiated. A 10‐day‐course treatment with remdesivir began on Day + 26.

FIGURE 1.

Chest computer tomography showing “ground‐glass” opacities consistent with COVID‐19 infection

We trended inflammatory parameters daily (Table 1), and based our treatment decision on a calculated H‐score ⁵ of 209, which correlated with a 92.8% risk probability of cytokine release syndrome. Two doses of tocilizumab and one unit of CCP ¹² were given. On Day + 32, severe hypotension, acute hypoxemia, and mildly increased right ventricle systolic pressure ensued, requiring mechanical ventilation and nitric oxide. A comprehensive evaluation for superimposed infections was remarkable for a repeated positive SARS‐CoV‐2 test, Staphylococcus epidermidis and Candida parapsilosis infections, and BK and cytomegalovirus viremias.

TABLE 1.

Inflammatory markers trend after starting treatment for COVID‐19 infection

		Inflammatory markers
COVID treatment day	Days posttransplant	Ferritin (ng/mL)	Procalcitonin (ng/mL)	LDH (U/L)	CRP (mg/dL)	D‐dimer (ug/mL FEU)
Day −2	24	7790	0.5	432	9.87	13.4
Day −1	25	14 167	0.68	626	10.8	18.31
Start of treatment [Link] , [Link]	26	14 272	1.04	780	11.8	17.11
Day 2 c	27	13 619	2.39	1019	16.2	16.5
Day 3 d	28	13 871	1.65	1092	8.9	13.6
Day 4	29	10 532	1.18	1021	4.2	11.62
Day 5	30	8797	0.66	962	2.3	9.67
Day 6	31	8496	0.51	1018	1.7	10.62
Day 7	32	6594	0.33	827	1.1	8.9
Day 8	33	6533	0.18	857	0.7	8.45
Day 9	34	5153	0.45	719	1.1	12.99
Day 10 e	35	4971	0.7	629	4.5	10.55
Day 11	36	6066	0.57	645	4	5.96
Day 12	37	5145	0.64	801	5.2	8.13
Day 13	38	4648	0.69	945	5	8.39
Day 14	39	6588	0.85	1208	4.2	7.92
Day 15	40	8727	0.81	1140	3	7.09
Day 16 f,g	41	10 294	1.5	1136	2.3	8.01
Day 17	42	28 884	2.99	1093	2.2	9.33

Note. Highest values are highlighted for each inflammatory marker.

^a First dose of remdesivir.

^bFirst dose of tocilizumab.

^c Second dose of tocilizumab.

^d First convalescent plasma transfusion.

^e Treatment with remdesivir completed.

^fThird dose of tocilizumab.

^gSecond convalescent plasma transfusion.

Bone marrow aplasia, lack of donor marrow CD33+ cells, absence of donor‐specific antibodies, and compatible forward and backward flow cytometric crossmatches confirmed primary graft failure and immune rejection, commonly seen in patients with IPEX syndrome. In preparation for a second haploidentical related CD34+ selected peripheral hematopoietic stem cell infusion, conditioning with fludarabine for 3 days began on Day + 39 posttransplant. Salvage therapy with a second unit of CCP and a third dose of tocilizumab was given on Day + 41. However, despite all efforts, he died on Day + 42 posttransplant.

Compared to their immunocompetent counterparts, immunocompromised patients with COVID‐19 are at increased risk for secondary infections and progression to severe disease, as well as a different response to supportive care measures. ⁶ Studies have shown that SARS‐CoV‐2 acts mainly on T‐lymphocytes; hence, a severely immunocompromised patient experiences a poorer outcome. A case report depicted two adult posttransplant patients with adequate graft function, on immunosuppressive therapy, that eventually died after developing multiorgan failure. ⁷

Our patient was treated aggressively, and we attributed the first decreasing trend in inflammatory markers (Table 1) to achieving disease control. However, the combination of graft failure, COVID‐19 infection with multiorgan failure, and opportunistic infections contributed to his death. We hope that new treatments continue to stem from ongoing research, to achieve a different outcome in our patient population.