PMC8712433_01
(A) Chest CT examination at admission showed no obvious abnormalities. (B) Chest CT showed a few scattered vague exudates and small nodules at midnight on the 26th day of admission before the patient was transferred to the medical intensive care unit (MICU). (Ca) Bedside chest radiograph showed consolidations, bilateral involvement, peripheral distribution, lower zone dominance, and reduction in lung volume on the third day in MICU. (Cb) Bedside chest radiograph showed lung lesions were significantly improved on the eighth day in MICU. (D) Abdominal color Doppler ultrasound reported fatty liver, alcoholic liver disease, dilated portal vein, and hepatosplenomegaly and ascites at admission.
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Chest CT examination showed no obvious abnormalities ( Figure 1A ). However, during this period, in the case of blood transfusion, Hb showed a significant reduction with increasing Ret ( Figures 3C, D ), Platelet (PLT) was still maintained at a significantly low level, and the bilirubin gradually increased, and prothrombin activity (PTA) and concentration of fibrinogen (FIB) gradually decreased ( Figure 3A  and  Supplementary Material Table 1 ). Chest CT showed a few scattered vague exudates and small nodules ( Figure 1C ). Bedside chest radiograph showed "consolidations, bilateral involvement, peripheral distribution, lower zone dominance and reduction in lung volume" ( Figure 1Da ). Bedside B-ultrasound showed a left ventricular ejection fraction (EF) of 65%. Since the WBC count and serum levels of CRP, PCT, IL-6, galactomannan, and beta-1,3-glucan did not change much and lung lesions were significantly improved ( Figure 1Db ), bacterial and fungal infections were not considered at that moment; disseminated B19 infection besides previously confirmed infection in the blood and lung was suspected.
(Aa) Blue-purple ecchymosis on the proximal right upper limb of the patient when being transferred to medical intensive care unit (MICU). (Ab) Blue-purple ecchymosis did not appear on his trunk, lower limbs, and upper left limb at that time. (Ba) Strained blisters filled with serous fluids on predominantly erythematous skin on his torso (Ba; buttocks as a representative) and limbs [(Bb); left limb as a representative] on the tenth day in MICU. (Ca) Bone marrow examination on the fourth day of admission (smear; x400) revealed active bone marrow hyperplasia; a significant increase of red blood cells (RBCs) (52.25%) of which the middle and late stages of RBC account for a large proportion; no obvious abnormalities of granulocytes; lymph proportion was reduced with the morphology roughly normal; platelets were significantly reduced and distributed in single or clusters, with no clue to acute aplastic crisis or hemophagocytic syndrome. (Cb) Bone marrow examination on the second day in MICU (smear; x400) revealed a marked decrease in the density of erythroblasts, inhibition of megakaryocyte maturation, and easily seen phagocytes containing vacuoles, platelets, impurities, and other components (black arrow).
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Bone marrow smears suggested HA without AAC or HPS ( Figure 2Aa ). At midnight on the 26th day of admission, the patient's temperature suddenly reached 40.7 C ( Figure 3A ), and the blue-purple ecchymosis on his proximal right upper limb enlarged ( Figure 2Ba ), however, Blue-purple ecchymosis did not appear on his trunk, lower limbs and upper left limb (including the catheterization sites of arteries and veins,  Figure 2Bb ). The results indicated the diagnosis of AAC with HPS ( Figure 2Ab ). On the tenth day in the MICU, his torso and limbs developed strained blisters filled with serous fluid on predominantly erythematous skin ( Figures 2Ca  and  Cb ).
(A) The distribution of the main clinical events and body temperature of the patient on the time axis. (B-E) The Ret count, Hb, WBC, and TBIL values of the patient on the time axis. P1, day 1 pre-hospital; P2, day 2 pre-hospital; D1 to D39, day 1 to day 39 of hospital admission; AH, alcoholic hepatitis; HA, hemolytic anemia; ARDS, acute respiratory distress syndrome; HPS, hemophagocytic syndrome; AAC, acute aplastic crisis; Ret, reticulocytes; Hb, hemoglobin; WBC, white blood cell; TBIL, total bilirubin.
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On the 10th day of admission, he received a transfusion of 2 units of washed RBC for Hb<60 g/L ( Figure 3A ). From this day to the 25th day of admission, he received meropenem instead of cefoperazone/sulbactam sodium as an empirical antibacterial treatment, and his highest body temperature dropped from 39.6 C to 38.2 C after 2 days, and then his fever was maintained at a low level ( Figure 3A ). Table1  and  Figure 3B ), and serum levels of CRP, PCT, beta-1,3-glucan, and galactomannan did not change much compared with those of before, and the serum IL-6 level was slightly higher ( Supplementary Material Table 1 ). The WBC count in ascites was lower, with a higher proportion of granulocytes. However, during this period, in the case of blood transfusion, Hb showed a significant reduction with increasing Ret ( Figures 3C, D ), Platelet (PLT) was still maintained at a significantly low level, and the bilirubin gradually increased, and prothrombin activity (PTA) and concentration of fibrinogen (FIB) gradually decreased ( Figure 3A  and  Supplementary Material Table 1 ). At midnight on the 26th day of admission, the patient's temperature suddenly reached 40.7 C ( Figure 3A ), and the blue-purple ecchymosis on his proximal right upper limb enlarged ( Figure 2Ba ), however, Blue-purple ecchymosis did not appear on his trunk, lower limbs and upper left limb (including the catheterization sites of arteries and veins,  Figure 2Bb ). On the eighth day in the MICU, the patient again had a high fever (40 C) ( Figure 3A ), and scattered purple-red ecchymosis appeared on his limbs and trunk, which was initially considered to be related to poor liver and coagulation function. HF symptoms worsened, with the appearance of pink foamy serous sputum and shock needing vasoactive drugs (norepinephrine 0.2-0.4 mug/kg/min and dopamine 5-10 mug/kg/min) to maintain BP at 77-110/22-77 mmHg. His family gave up, and the patient was transferred to the local hospital, where he died the next day ( Supplementary Material Table1  and  Figure 3 ).
(A) Next-generation sequencing (NGS) results of blood collected at 8 h after the patient was transferred to the medical intensive care unit (MICU) reported extremely high DNA copies of B19 (1,605,726 copies/microg DNA, and the relative abundance was 99.99%). (B) NGS results of bronchoalveolar lavage fluid (BALF) collected on the third day in MICU reported high DNA copies of B19 (15,938 copies/microg DNA, and the relative abundance was 97.85%). (C-F) Real-time PCR confirmed positive results of B19 in bone marrow, gastric juice, BALF, and urine collected on the eighth day in MICU. (G-J) Real-time PCR confirmed positive results of B19 in skin blister fluid, sputum, and blood collected on the eighth day in MICU. (J) Real-time PCR showed that the previously positive result of B19 in urine became negative in the urine sample collected on the tenth day in MICU.
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The next day, the NGS results reported extremely high DNA copies of B19 (1,605,726 copies/microg DNA, and the relative abundance was 99.99%) ( Figure 4A ). PCR. Positive results of all the specimens ( Figures 4C-F ) confirmed the correctness of inference. Bullous pemphigus-related anti-desmosomal core glycoprotein 1,3 antibodies (Dsg1 and Dsg3) and structural components of the hemidesmosome (BP180) were all negative, while real-time PCR confirmed B19 positivity in the skin blister fluid ( Figure 4G ), sputum ( Figure 4H ), and blood ( Figure 4I ), although the B19 DNA in the urine became negative ( Figure 4J ).