A thirteen-year-old boy with IFNAR1 deficiency was admitted to Bushehr Khalij Fars Hospital, Bushehr, Iran, in April 2021. He presented with upper respiratory tracts infection symptoms, such as runny nose, itchy throat, and low-grade fever for 11 days, followed by sweating and high-grade fever in the last three days. The patient only had a history of meningitis after getting vaccinated for MMR at 12 months of age. He was a suspected case of COVID-19, confirmed by a positive COVID-19 polymerase chain reaction (PCR) test. The treatment was initiated with favipiravir; however, the patient showed no response to the therapy, and his symptoms worsened, including shortness of breath and persistent fevers. Therefore, he was admitted to the pediatric intensive care unit (PICU). The result of high-resolution computed tomography (HRCT) scanning revealed lung involvement of 70% with extensive areas of consolidation in both lungs and patchy consolidation in the base of the lungs (see Fig. 1). The result of his echo test was normal. The oxygen saturation (SpO2) of the patient at the first emergency department visit was 94% but decreased to 90% within the first days after hospitalization.
After hospitalization, the patient received vancomycin, piperacillin, tazobactam, aspirin, famotidine, zinc, vitamin C, IFN-γ, remdesivir, and methylprednisolone pulse (30mg/kg). Two days after hospitalization, the patient’s fever persisted, and the antibiotics were switched to colistin and teicoplanin, and caspofungin was added to his medications. Although the level of IL-6 was high in the patient’s serum, tocilizumab was not initiated for the patient due to the prolonged prothrombin time (PT) and partial thromboplastin time (PTT) (see Table 1). Because of the critical condition of the patient, he received one dose (1gr/kg) of intravenous immune globulin (IVIG). The patient also received IFN-γ (50µg/m2) between the third and sixth days of hospitalization (4 doses).
Table 1
Test | Result | Ref. range/Unit | Test | Result | Ref. range |
WBC | 13.2→14.2→9.9 | 4.8–10.8 10^3/µL | K | 4.2 | 3.5–5.5 mEq/L |
RBC | 4.5 | 4.5–6.5 10^6/µL | BUN | 19 | 6–23 mg% |
Hb | 12 | 13.5–18 g/dL | Creatinine | 0.9 | 0.7–1.4 mg% |
PLT | 244 | 150–450 10^3/µL | Calcium | 9.3 | 8.6–10.3 mg/dL |
ESR | 70→89→70 | 0–15 m.m/h | Phosphorus | 3.1 | 3.2–5.7 mg/dL |
IL-6 | 36 | < 6.6 pg/mL | ALT | 49 | 5–40 IU/L |
PT | 14.6→17.2→16.1 | 11–14 sec | ALP | 400 | 35–130 IU/L |
PTT | 47.7→38.1→38.1 | 25–40 sec | Bilirubin total | 0.5 | 0.3–1.2 mg/dL |
INR | 1.36→1.24→1.16 | 0.8–1.2 | Bilirubin direct | 0.1 | < 0.3 mg/dL |
Na | 136 | 136–145 mEq/L | CPK | 53 | 10–120 µg/L |
WBC, white blood cell; RBC, red blood cell; Hb, hemoglobin; PLT, platelet; ESR, erythrocyte sedimentation rate; PT, prothrombin time; PTT, partial thromboplastin time; INR, international normalized ratio; IL−6, interleukin−6; BUN, blood urea nitrogen; ALT, alanine transaminase; ALP, alkaline phosphatase; CPK, creatine kinase. |
On the fifth day of hospitalization, the patient had bradycardia and hypertension; however, the second echo test and cardiology consultation were normal. Atropine was prescribed for the patient to be used in case the heart rate falls below 40 beats/min. The eye examination showed no papilledema, but pseudotumor cerebri was suspected. Therefore, remdesivir and methylprednisolone pulse were discontinued. After the fifth day of hospitalization, his fever was reduced, and his general condition improved on the sixth day of hospitalization. The SpO2 of the patient increased to 94% with nasal cannula oxygen therapy (with a flow of 6 liters/min). The antibiotic therapy was continued for ten days, and the patient received fresh frozen plasma (FFP) (10cc/kg) to treat his prolonged PT and abnormal international normalized ratio (INR). During hospitalization, the patient had recurrent panic attacks that led to a lower SpO2 below 90%. Hence, the psychologist prescribed risperidone, \(\frac{1}{4}\) pill every night.
Eight days after hospitalization, the patient had a good general condition and was moved to the ward from PICU. On the ninth day of hospitalization, the patient’s SpO2 was above 94% without oxygen therapy, and two days later, he was discharged from the hospital.
IFNAR1 deficiency
The presented case was born to consanguineous parents and had a sister who passed away after getting vaccinated for MMR. As mentioned before, the patient had a history of meningitis after getting vaccinated for MMR at 12 months of age that led to his recurrent hospitalization due to fever twice a year. The periodic neutropenia disorder was suspected in the patient. Therefore, to find the underlying genetic cause of the disease, whole exome sequencing (WES) was performed as previously described [7]. The result of WES (see Table 2) revealed a novel homozygous mutation in the IFNAR1 gene at the splicing site of exon 6 (NM_000629 Exon6:c.674(-2b)A>G). The Sanger sequencing analysis indicated that the parents, as expected, were heterozygous for such mutation. However, given the function of IFNAR1, the high effect of splicing mutation and heterozygosity of parents, the causative effect of this mutation on the disease is highly suggested.