Abstract
SARS coronavirus (SARS-CoV-2) since the year 2020 has been affecting people of all age groups involving all systems possible. The effect of COVID-19 on hematological system has been commonly seen in the form of cytopenia, prothrombotic states, or disorders of coagulation, but it has been rarely implicated as a causal factor for hemolytic anemia in children. We present a 12-year-old male child who presented in congestive cardiac failure due to severe hemolytic anemia caused by SARS-CoV-2, with hemoglobin falling to a nadir of 1.8 g/dL. Child was diagnosed as a case of autoimmune hemolytic anemia and managed with supportive management and long-term steroids. This case highlights one of the lesser known effects of the virus, causing severe hemolysis and the role of steroids in its treatment.
Keywords: COVID-19, SARS-CoV-2, Child, Hemolysis, Anemia
Introduction
COVID-19 caused by SARS coronavirus (SARS-CoV-2) presents in myriad ways in children, ranging from asymptomatic to hyperinflammatory condition such as multisystem inflammatory syndrome (MIS-C) involving with respiratory, neurological, gastrointestinal, and hematological manifestations.1 It affects the hematological system in form of cytopenia, prothrombotic states, or disorders of coagulation, which have been well described in adults, but only a few cases of autoimmune hemolytic anemia due to COVID-19 infection described in children.2,3
Case report
A 12-year-old male child patient, first product of a third-degree consanguineous marriage, developmentally normal, a known case of bilateral profound sensorineural hearing loss with cochlear implant in situ, presented with fever and cough of 7-day duration, and lethargy of 1-day duration in May 2021 (during second wave of COVID-19 pandemic). Fever was intermittent, low grade, responding to antipyretics; cough was mild, nonproductive, but since last one day, child was found to be lethargic. There was no history of pain abdomen, vomiting, breathlessness, or discolored urine. There was no history of any drug intake known to cause oxidative hemolysis. No history of previous blood transfusion, with last known hemoglobin of 11.8 g/dL 1 month back. Child's mother also had fever, cough, and body ache for last 7 days.
On examination, child was found to be lethargic, temperature of 100.8 °F, tachypnea with respiratory rate of 38 per minute, pulse rate of 130 per minute, thready pulse with blood pressure 88/50 Hg (<5th centile), SpO2- 96% on room air, severe pallor, icterus with raised Jugular Venous Pressure (JVP). There was no lymphadenopathy, conjunctival congestion, mucosal erythema, or rash. He was found to have short stature with height of 128 cm (<3rd centile) and weight of 30 kg (10th centile), and BMI 18.3kg/m2 (50th to 23e). On systemic examination, respiratory system revealed mild intercostal retractions and bilateral fine basal crepitations, cardiac evaluation revealed hyperdynamic precordium with S3 gallop. As per abdominal examination, liver was found to be palpable 4 cm below the right costal margin in mid clavicular line, which was soft in consistency, nontender with smooth surface and a span of 12 cm, and spleen palpable 5 cm below the left costal margin, which was also soft in consistency.
Child was admitted in pediatric ICU (COVID-19 suspect zone) and managed as a case of congestive heart failure, with IV antibiotics, IV fluids, IV diuretics, respiratory support by heated humidified high flow nasal cannula and nor-epinephrine infusion. On admission, the child was found to have hemoglobin of 1.8 g/dL; there were no features of COVID-19 pneumonia on chest radiography. Samples were sent for anemia workup, and O negative Packed Red Blood Cell (PRBC) transfusion was given (incompatible crossmatch was found with every blood group type, even with O negative PRBCs, DAT ++++, due to unavailability of facility typing it as IgG or C3/C4 type could not be done). On evaluation, the child had features suggestive of severe autoimmune hemolytic anemia (mixed type) (Table 1) and was thus started on high-dose steroid therapy.
Table 1.
Investigations at the time of admission.
| Laboratory test | Result | Reference Range |
|---|---|---|
| Hemoglobin | 1.8 g/dL | 12.5–16.1 g/dL |
| Hematocrit | 1.6% | 35–45% |
| RBC count | 0.14 mil/cmm | 4–5.2 mil/cmm |
| MCV | 115.7 fL | 78-95 fL |
| MCH | 12.86 pg | 26–32 pg |
| MCHC | 72.5 g/dL | 32-36 g/dL |
| RDW | 24.7% | 12–14% |
| WBC count | 12,400/cmm | 4000-10500/cmm |
| Differential count | Poly- 74%, Lympho 20% Monocytes 4%, Basophils 2% |
– |
| Platelet count | 2,00,000/cmm | 1,50,000–4,00,000/cmm |
| Direct Coombs test | ++++ | – |
| Reticulocyte count | 8% | 0.5–1.5% |
| Reticulocyte index | 0.49 | 1–3 |
| Peripheral blood smear | RBC agglutination seen with microcytes, ovalocytes, occasional spherocytes and tear drop cells | – |
| Total bilirubin | 4.3 mg/dL | <1 mg/dL |
| Indirect bilirubin | 4.1 mg/dL | – |
| ALT | 45 U/L | 5–45 U/L |
| AST | 34 U/L | 10–40 U/L |
| Lactate dehydrogenase | 640 U/L | 120–330 U/L |
| D-dimer | 10 ng/mL | 0.02–200 ng/mL |
| CRP | 0.1 mg/dL | 0.08–0.76 mg/dL |
| Procalcitonin | 0.48 ng/mL | <0.5 ng/mL |
| INR | 0.98 | 0.8–1.2 |
| pro-BNP | 130 pg/mL | 0–100 pg/mL |
| IL6 | 5.8 pg/mL | 0.31–5.0 pg/mL |
| HIV serology | Non-reactive | – |
| Anti-HCV | Negative | – |
| C3 levels | 0.98 g/L | 0.90–1.80 g/L |
| ANA (by indirect immunofluorescent assay) | Positive (1+), in nucleus speckled pattern | – |
| Malaria | Negative ICT, QBC, thin and thick smear | – |
| Dengue | Negative NS1, IgM, IgG | – |
| Leptospira | Negative IgM and IgG | – |
| TyphiDot | Negative | – |
| COVID-19 | Positive RT PCR on throat swab | – |
| Urine routine | Reddish with Protein (+), positive of blood (++) and positive (+) for bilirubin | – |
| Urine microscopy | 1-2 pus cells and 3–4 RBCs | – |
| Ultrasound abdomen | Hepatosplenomegaly with liver sized 12.7 cm and spleen sized 10.2 cm | – |
| Blood culture | No growth | – |
During this admission, he was transfused seven times with a total of 50 ml/kg PRBC transfusion over the initial 7 days of presentation (Fig. 1). As the reticulocyte index was calculated to be 0.49 (<3), once the child was stabilized, a bone marrow aspiration and biopsy was done to rule out ineffective hematopoiesis and secondary causes of hemolysis, which revealed hypercellular marrow with erythroid hyperplasia with megaloblastic change, with no features of hematological malignancy. He was given pulse therapy of Inj Methyl Prednisolone at 30 mg/kg for 2 days, followed by high-dose Inj Methyl Prednisolone 8 mg/kg for 5 days, followed by oral Prednisolone. Child showed gradual improvement over 7 days of intensive care and was discharged after 11 days of admission on oral prednisolone at 2 mg/kg/day for 4 weeks, which was slowly tapered off over 9 months (in view of Direct Coombs test positivity persistent, though gradually reducing, till 7 months of presentation). Post initial admission, the child did not require any admission or repeat blood transfusion. His extractable nuclear antigen/antinuclear antibodies assay on recovery was found negative. On follow-up at 1 year postpresentation, he is thriving well, with posttreatment Hb of 12.5 g/dL, with Mean Corpuscular Volume (MCV) 90 fL, MCH 31.7 pg, MCHC 33.5 g/dL with normocytic normochromic morphology. His hepatomegaly and splenomegaly had completely regressed. He was further evaluated for short stature revealing growth hormone deficiency and has been started on the GH replacement therapy. Genetic workup for syndromic association could not be done due to financial limitations of the family. Patient/parent consent was obtained for inclusion of data in the study.
Fig. 1.
Trend of hemoglobin.
Discussion
Hemolytic anemias form an important subset of causes of anemia in children, which may be classified as immune or non-immune-mediated hemolysis. Among the autoimmune hemolytic anemias (AIHA), warm reactive AIHA accounts for 60–90% of primary AIHA and cold agglutinin disease amounting to around 10%. The Coombs test establishes the diagnosis of AIHA, with positive result with anti-IgG or both anti-IgG and anti-C3 in warm agglutinin AIHA, and positive result with anti-C3 and negative with anti-IgG in cold agglutinin AIHA.3 On peripheral smear, cases of warm AIHA have spherocyte dominance which may cause high MCHC, whereas cold agglutinin disease has aggregated red cells which can cause spuriously elevated MCV, low hematocrit (with respect to hemoglobin levels) and low RBC count.4, 5, 6, 7 The hemolysis in cases of warm AIHA is extravascular (mainly in spleen) and in cases of cold AIHA can be both intravascular and extravascular (mainly in liver).3 In our case, antibody-specific Coombs test could not be done due to unavailability of the test, but the peripheral blood picture, the red cell indices, and splenomegaly pointed toward a mixed AIHA.
Etiologically, almost half of the cases of warm AIHA are due to unknown causes and the other half are secondary to immunological or lymphoproliferative disorders. In cases of cold agglutinin disease, lymphoproliferative malignancies, and infections (mycoplasma, Epstein-Barr Virus (EBV), syphilis) are important subgroup of secondary causes.3,4
Among the infective etiology, COVID-19 has been associated with autoimmune hematological manifestation, most common being immune thrombocytopenia and autoimmune hemolytic anemia and a few cases of warm AIHA.3,8, 9, 10 But only a few cases of autoimmune hemolytic anemia due to COVID-19 infection in pediatric population have been reported.2,11
Glucocorticoids have been described as the mainstay of treatment, with better response in warm AIHA, and may be required to be continued for 6–12 months. In patients not responding to glucocorticoids, treatment in the form of IVIG or Rituximab may be used. Splenectomy may also be done in cases refractory to other modalities.3,12,13 Blood transfusion as a supportive therapy is to be given with discretion and are recommended only in cases of life-threatening anemia, with caution.3
Autoimmune hemolytic anemia varies in severity, ranging from mild self-limiting disease to life threatening with mortality in around 4% cases. Approximately 30% of cases have chronic hemolysis, often with an underlying pathology. Most favorable prognosis is found in children with primary AIHA associated with infections.4,6
Unavailability of antibody-specific Coombs test and genetic evaluation (on follow-up) was significant limitation in the complete workup of the patient.
Lessons learned
-
•
COVID-19 is a common infection in children, which though known to affect children mildly, may present as severe autoimmune hemolytic anemia.
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•
Early initiation of steroids leads to early hematological recovery.
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•
Child may require steroid therapy for long duration.
Patients/ Guardians/ Participants consent
Patients informed consent was obtained.
Ethical clearance
Not Applicable.
Source of support
Nil.
Disclosure of competing interest
The authors have none to declare.
Acknowledgements
None.
References
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