Cases (Summarized in Table 1)

Cases (Summarized in Table 1)

Case−1

A 30-year-old man with sickle cell disease underwent a matched related donor (MRD) allogeneic stem cell transplantation (allo-SCT) for recurrent vaso-occlusive crises (VOC), sickle cell hepatopathy, and a prior history of stroke. He was admitted during the month of January for planned conditioning. At admission, respiratory viral screening by quadriplex nasopharyngeal aspirate (NPA) PCR was negative for respiratory syncytial virus (RSV).

 | Case−1 | Case−2 | Case−3
Host | 30 year old male with MRD-Allo-SCT, for SCD | 19 year old male with Haplo-SCT, for SCD | 19 year old female with Haplo-SCT, for SCD
Height/Weight | 183 cm, 81 kg | 166 cm, 80 kg | 152 cm, 38 kg
Conditioning Regimen | Alemtuzumab, TBI | ATG, Thiotepa, Cyclocphosphamide | ATG, Thiopeta, Fludaribine, Cyclophosphamide, TBI
GVHD Prophylaxis | Sirolimus | Sirolimus | MMF, Sirolimus
Engrafement Day | D + 17 | D + 25 | Not engrafted
Timing of infection (RSV PCR Positive) | Day – 3 | Day + 2 | Day – 4
Ribavirin Dose | 400 mg BID (10 mg/kg/day) | 600 mg PO TID (maximum dose) | 200 mg PO TID (15 mg/kg/day)
Ribavirin Duration (days) | 7 days | 10 days | 21 days
Palivuzumab dose | 1000 mg IV(12 mg/kg) | 1200 mg IV(15 mg/kg) | 600 mg IM(15 mg/kg)
Disease stage at Palivizumab administration | URTI | URTI | LRTI
Safety (any reported allergy or side effects) | None | None | None
ISI-RSV Score: | 4/12 (Moderate) | 8/12 High | 8/12 (High)
−ANC < 0.500 | 16.7 (0/3) | 0.0 (3/3) | 0.0 (3/3)
−ALC < 0.200 | 0.0 (3/3) | 0.0 (3/3) | 0.0 (3/3)
−Age > 40 years | No (0/2) | No (0/2) | No (0/2)
−MA regimen | No (0/1) | Yes (1/1) | Yes (1/1)
−GVHD | No (0/1) | No (0/1) | No (0/1)
−Steroid within 30 days | No (0/1) | No (0/1) | No (0/1)
−Pre-engraftment or recent engraftment within 30 days | Yes (1/1) | Yes (1/1) | Yes (1/1)
Symptom’s onset or PCR positive to treatment: |  |  | 
−To RBV | 2 days | 2 days | 3 days
−To IVIG | 2 days | 4 days | 8 days
−To Palivizumab | 6 days | 4 days | 8 days
Hospital Length of Stay | 14 days | 92 days | 38 days
Outcome RSV PCR | No repeat | Persistent shedding | Persistent shedding
Outcome ICU admission | No | No | Yes
Outcome Survival at 30 days | Survived | Survived | Died D + 40 due to pulmonary mucormycosis

On day 2 of admission, conditioning was initiated with alemtuzumab for 5 days, in addition to total body irradiation (TBI) and sirolimus. On the final day of alemtuzumab administration, he developed a dry cough, sore throat, fever, and shortness of breath. Despite these symptoms, he remained clinically stable on room air without respiratory distress. Respiratory viral panel PCR performed on the same day was positive for RSV (transplant day – 3). Laboratory evaluation showed a white blood cell count of 17.3 × 10⁹/L, and chest radiography was unremarkable. His ISI-RSV score was 4 out of 12 (moderate risk of progression).

Treatment with oral ribavirin 600 mg thrice a day was initiated on transplant day −1 (admission day 9) and continued for 7 days, together with intravenous immunoglobulin (IVIG) 10% at a dose of 30 g daily for 4 days. Allogeneic stem cell infusion was performed on transplant day 0 (admission day 10). A single dose of palivizumab 1000 mg (intravenous) was subsequently administered on transplant day + 2 (admission day 12; infection day 6).

During follow-up, the patient's respiratory symptoms gradually improved. He remained afebrile, maintained adequate oxygenation on room air, and demonstrated stable respiratory and hemodynamic status throughout hospitalization. He was discharged two weeks later in good clinical condition and continues to be followed regularly without significant complications to date.

Case−2

A 19-year-old man with sickle cell disease underwent haploidentical allogeneic stem cell transplantation (haplo-allo-SCT) for recurrent episodes of acute chest syndrome. He was electively admitted in the month of December for transplantation and began conditioning on admission day 2 with antithymocyte globulin (ATG), thiotepa, and cyclophosphamide. Stem cell infusion was performed on admission day 9 (transplant day 0), after which sirolimus was initiated for graft-versus-host disease prophylaxis.

On transplant day + 2, he developed febrile neutropenia accompanied by productive cough, abdominal pain, and diarrhea. He remained hemodynamically stable and maintained adequate oxygenation on room air throughout this period. Diagnostic workup revealed a positive respiratory viral panel for respiratory syncytial virus (RSV), while gastrointestinal multiplex PCR was positive for Salmonella species. Blood cultures remained negative, and chest radiography showed no acute abnormalities. Empiric antimicrobial therapy with meropenem and vancomycin was initiated. The ISI-RSV score was 8 out of 12 (high risk of progression).

On transplant day + 4, oral ribavirin 600 mg twice daily was added and continued for 10 days. Adjunctive therapy included a single dose of palivizumab administered on transplant day + 6, along with daily intravenous immunoglobulin (IVIG) for four consecutive doses.

Over the subsequent days, both respiratory and gastrointestinal symptoms gradually improved, and the fever resolved by transplant day + 8 despite ongoing neutropenia. Repeat quadriplex PCR on transplant day + 9 remained positive for RSV, with a cycle threshold (Ct) value of 24.7. Neutrophil engraftment occurred around transplant day + 24; however, persistent RSV shedding was documented until transplant day + 43, at which time the Ct value had increased to 30.

The remainder of his hospitalization was complicated by hospital-acquired pneumonia, possible invasive fungal pulmonary infection, and hemorrhagic cystitis requiring treatment with cidofovir. He was ultimately discharged in good clinical condition after a 92-day hospital stay and continues to be followed regularly in the outpatient clinic with a favorable clinical outcome to date.

Case−3

A 19-year-old woman with sickle cell disease was admitted in the month of September for haploidentical allogeneic stem cell transplantation (haplo-allo-SCT) due to recurrent acute chest syndrome. Admission RSV screening PCR was negative (transplant day −9), and conditioning was initiated with ATG, thiotepa, fludarabine, and cyclophosphamide.

On transplant day −4, she developed cough and shortness of breath and was diagnosed with RSV infection based on positive PCR from nasopharyngeal swab, in addition to concurrent Clostridioides difficile and enterotoxigenic Escherichia coli (ETEC) gastrointestinal infections. The ISI-RSV score was 8 (high risk of progression), and hence oral ribavirin was initiated on transplant day −1; the dose was ribavirin 200 mg every 8 h for 7 days.

Following stem cell infusion, her post-transplant course was complicated on transplant day + 1 by febrile neutropenia, persistent diarrhea, and progressive respiratory symptoms. Initial imaging demonstrated mild bilateral pulmonary infiltrates and pansinusitis without evidence of invasive fungal disease (Fig. 1A & 1B). Despite broad-spectrum antimicrobial therapy, fever and cough worsened, prompting treatment with IVIG and intramuscular palivizumab on transplant day + 4. Fever resolved by transplant day + 5, and her symptoms initially improved.

Fig. 1: A: Case−3, Transplant Day – 3, Chest X-ray showing no evidence of lower respiratory tract infection, B: Case−3, Transplant Day + 3, CT chest illustrating minimal ground glass changes over the left lung. C: Case−3, Transplant D + 8, CT chest shows progressive increase in the infiltration and ground glass opacitities bilaterally. D: Case−3, Transplant Day + 19, CT chest demoonestrates further progression of bilateral consiliration and nodular opacitites.

However, by transplant day + 8, she developed worsening cough and new oxygen requirements, accompanied by radiologic progression of bilateral pulmonary infiltrates and worsening pansinusitis (Fig. 1C & D). Antimicrobial and antifungal therapy were escalated, including liposomal amphotericin B.

On transplant day + 12, she developed foul-smelling nasal discharge, and MRI findings raised concern for invasive fungal sinusitis. Prompt endoscopic examination for the sinuses by ENT showed no compelling evidence of invasive fungal infection, but biopsies for culture were obtained. Due to that, further empiric escalation of anibacterial coverage (ceftazidime-Avibactam + Amikacin).

Her condition further deteriorated by transplant day + 19, requiring intensive care admission and high-flow nasal oxygen support. Bronchoscopy was declined by the patient, and evaluation suggested a hyperinflammatory syndrome with markedly elevated ferritin and interleukin−6 levels, for which she received methylprednisolone and tocilizumab, resulting in transient clinical improvement and was sent back to the floor. Ribavirin was subsequently extended three weeks duration.

On transplant day + 26, she experienced recurrent rapid respiratory failure requiring re-admission to the intensive care unit, high-flow oxygen therapy, and eventual mechanical ventilation. Subsequent tracheal aspirate fluid revealed fungal elements on respiratory cytology consistent with mucormycosis (Fig. 2A & B), despite ongoing liposomal amphotericin B therapy, leading to the addition of isavuconazole. Fungal culture subsequently came back negative. Cardiac evaluation demonstrated reduced left ventricular systolic function, raising concern for myocarditis. Persistent RSV positivity in the setting of delayed engraftment prompted additional treatment with palivizumab and IVIG (second course).

Fig. 2: A: Case−3, Grocott methenamine silver (GMS) staining of tracheal aspirate, showing broad, ribbon-like, non-septate hyphae consistant with mucormycosis. B: Case−3, Transplant Day + 38, chest X-ray with extensive bilateral consolidative and nodular changes.

Despite maximal supportive care and broad antimicrobial treatment, her respiratory failure progressed, and she died on transplant day + 38, approximately six weeks after RSV diagnosis.