Life-Threatening Recurrence of Paroxysmal Cold Hemoglobinuria in a Child During Influenza A Infection

Autoimmune hemolytic anemias (AIHAs) include warm AIHA, cold agglutinin disease, and paroxysmal cold hemoglobinuria (PCH). Paroxysmal cold hemoglobinuria is the least of the AIHAs, accounting for <5% of AIHA cases. Although tertiary syphilis was the underlying trigger of PCH in more than 90% of the cases in the early 1900s, PCH is nowadays almost exclusively observed in young children with a concurrent or recent viral infection.^1-3 This observation may be explained by a possible antigenic modification of the erythrocyte membrane by the viruses resulting in the production of autoantibodies. Also, a dysregulation in the immune system such as production of autoantibodies by altered T suppressor function or immunologically competent abnormal cell clones may be the cause.^4,5

“Historical PCH,” associated with tertiary syphilis in adults, manifested as “paroxysms” of hemolytic anemia episodes. However, “modern PCH” occurs typically as a single hemolytic attack in young children,^1-4 although few cases with a recurrence have been reported in the literature.^6-9 We present here a very rare case of recurrent PCH resulting in severe life-threatening anemia during the course of influenza A infection.

An 8-year-old boy was admitted with acute onset “grape molasses-colored” urine, icterus, and abdominal pain. He had symptoms of an upper respiratory tract infection for 1 week, and developed fever reaching 40°C one day before his admission. There was no history of ingestion of fava beans. Abdominal ultrasonography revealed no abnormality. Dipstick examination of the urine confirmed hemoglobinuria. Table 1 shows the laboratory findings of the case. In the past history of the patient, a PCH hemolytic episode which occurred 18 months ago following a febrile upper respiratory tract infection was evident. At that time, hemoglobin (Hb) nadir was 9.8 g/dL and the case received only intravenous fluids. Complete remission occurred within 10 days. The boy remained free of any associated symptoms until the second episode.

Table 1.

Laboratory Data of the Patient at the Time of Paroxysmal Cold Hemoglobinuria Recurrence and During Follow-up

	Day 1	Day 2	Day 3	Day 4	Day 5	Day 8	Day 9	Day 14	Day 20	Day 41
Hemoglobin, g/dL (RR: 11.5-15.5)	13.4	7.3*	7.5*	5.6*	5.9	4.5	4.8	7.1	9.1	14.4
MCV, fL (RR: 77-95)	80.4	79.1	81.2	83.8	84.4	91.1	92.1	98.9	98.3	89.1
WBC count, K/µL (RR: 4.5-13.5)	9.7	7.5	9.0	16.5	17.4	12.9	7.4	7.8	5.7	4.4
Platelet count, K/µL (RR: 150-400)	185	123	150	165	137	200	220	201	215	211
Bilirubin, mg/dL (RR: 0.3-1.2)	5.8	9.3	8.2	7.1	4.7	NA	NA	1.16	0.72	NA
LDH, U/L (RR: 143-370)	1874	3358	3506	2215	1753	NA	NA	735	481	337
Creatinine, mg/dL (RR: 0.34-0.53)	0.93	1.00	0.91	0.82	0.75	NA	NA	0.56	0.39	NA

LDH, lactate dehydrogenase; MCV, mean corpuscular volume;NA,not available;RR,reference range; WBC, white blood cell.

*The patient received erythrocyte transfusion following this laboratory finding.

Following the hospitalization of the case due to the second hemolytic episode, we observed an abrupt decrease in Hb level from 13.4 g/dL to 7.3 g/dL on the second day (Table 1). The boy was transferred into the pediatric intensive care unit and received erythrocyte transfusion. In the follow-up, the urine color became lighter initially, however, it got darker again. The patient was transfused for the second time. In the laboratory examinations, the direct antiglobulin test (DAT) was found as 4+ for complement C3d and negative for immunoglobulin G (IgG). With this finding, we considered PCH the most probable diagnosis and kept the patient, his environment, and intravenously administered fluids warm.

Microscopic examination of the peripheral blood on the second day revealed spherocytes, agglutinations of few red cells, and relative reticulocytopenia initially, whereas polychromasia secondary to an increase in reticulocytes was observed after the third day. Notably, erythrophagocytosis by both neutrophils and monocytes was observed on the fourth follow-up day. Neutrophil erythrophagocytosis has been increasingly recognized as a feature of PCH in the literature.^10,11 A Donath–Landsteiner (DL) test was attempted, but the result was inconclusive due to hemolysis in the samples.

Polymerase chain reaction testing of the nasopharyngeal/throat specimen revealed positivity for influenza A virus. The child received erythrocyte concentrate for the third time which was warmed before transfusion.

In the follow-up, the urine color became clear, and elevated laboratory markers associated with hemolysis decreased gradually. Urine dipstick examination on the eighth day was negative for Hb. The child was discharged at the end of the second week in good clinical condition. The DAT repeated 40 days after admission was found to be negative. Laboratory data during the follow-up are also presented in Table 1.

Our case is atypical due to the recurrence of the PCH hemolytic episode. To our knowledge, only 4 cases of recurrent PCH in children have been reported so far.^6-9 The recurrence in those cases took place 7-22 months after the first hemolytic episode. The DL test was negative at the time of recurrence in 2 of those patients whose DAT was positive for C3d only, as was the case in our patient.^6,7

The underlying polyclonal IgG autoantibody in PCH usually binds to the P antigen on the red blood cell membrane at colder temperatures in the extremities along with the first 2 components of complement. When these erythrocytes reach the body core with a higher temperature, intravascular hemolysis occurs secondary to the activation of the complement cascade. In PCH cases, the DAT is usually positive for complement (typically reported as positivity for C3d) and negative for IgG.^1-3 The classical finding of DAT negativity for IgG in PCH cases may be explained by the dissociation of complement-fixing antibodies from the erythrocyte surface at warmer temperatures, leaving only the complement bound. In the present case with intravascular hemolysis, DAT positivity for only complement is consistent with the PCH diagnosis. Although the DL test is highly specific, its sensitivity to PCH is low. This may be due to an insufficient amount of complement initially and/or the transient characteristic of the DL antibody.^4,10 In fact, in a case with the typical clinical presentation of PCH, including acute onset of hemoglobinuria with an antecedent viral infection and the transient nature of the hemolysis, the DL test may not even be needed.

We also noted erythrophagocytosis by both monocytes and neutrophils on peripheral blood smears. Although erythrophagocytosis by monocytes may occur in some AIHAs, neutrophil erythrophagocytosis has been most strongly associated with PCH.^10,11 This phenomenon may be triggered by the attachment of antibody and complement to erythrocytes, making them an attractive target for neutrophils. Our case also had erythrocyte agglutination on blood smear, a finding reported in PCH, though less common than in cold agglutinin disease.^2,10,11

In PCH, acute hemolytic attacks are often severe and may necessitate leukoreduced erythrocyte transfusions, but supportive care suffices in most cases.^1-4 Although the benefits of actively warming the patients are not clear, avoiding cold exposure and warming intravenous fluids and, when indicated, erythrocyte concentrates before infusion are recommended.

In conclusion, we present here a rare case of PCH recurrence resulting in severe anemia. Paroxysmal cold hemoglobinuria may go undetected in a substantial proportion of cases due to its rarity and heterogeneity in both clinical and laboratory presentations of affected individuals. To our knowledge, no PCH case from Türkiye has been reported before in the literature. Families of children with a PCH episode and physicians should be informed about the rare possibility of recurrence and the associated signs and symptoms for which timely admission to a health care center is required. Finally, in a child with suspected PCH, the blood smears should be examined carefully and repeatedly for neutrophil erythrophagocytosis which may aid in the diagnosis.

Funding Statement

This study received no funding.