A 36-year-old farmer, who had been admitted 29 days ago to another hospital with severe COVID-19 pneumonia, presented to our emergency 13 days after discharge with complaints of fever (101.4 F) for 5 days, generalized weakness and loss of appetite for 4 days, progressive exertional dyspnea, and occasional dry cough for 2 days. He had no history of orthopnea, paroxysmal nocturnal dyspnea, pedal edema, hemoptysis, chest pain, burning micturition, or bowel complaints. He had been discharged from the last admission on home-based intermittent oxygen therapy at 2-4 L/min, multivitamins, and oral pirfenidone (an anti-fibrotic agent for post-COVID-19 pulmonary fibrosis) 200 mg three times a day (TDS). He had no history of substance abuse or chronic illness, and his family history was insignificant.
He was conscious, oriented, and febrile (102.8 F/39.3 C). His oxygen saturation was 93% under ambient air, a respiratory rate of 15 breaths per min, blood pressure of 108/76 mmHg, and a pulse rate of 108 beats per min. On systemic examination, hepatomegaly was present 2 cm below the right subcostal margin in the mid-clavicular line and bilateral end-inspiratory fine crepitations were auscultated in the chest. The rest of the systemic examination was normal.
On investigation, his random blood sugar was 203 mg/dL, TruNat swab for SARS-CoV-2 was reported negative, and arterial blood gas analysis showed Type 1 respiratory failure. His ECG showed sinus tachycardia, and the bedside chest radiograph showed bilateral ground-glass opacities (Figure 1A). A provisional diagnosis of post-COVID-19 sequelae with bilateral lower respiratory tract infection (LRTI) with Type 1 respiratory failure was made. Further investigations were sent. He was treated with low flow oxygen support, antipyretics, injectable ceftriaxone, intravenous fluids, and supportive care. His preliminary blood investigations showed pancytopenia with reduced reticulocyte count and transaminitis [Hb-9.2 g/dL, TLC-3,400 cells/mm3, platelets-20,000 cells/mm3, corrected reticulocyte count < 0.5%, peripheral smear-pancytopenia, serum AST-4688 U/L, ALT-6680 U/L, serum bilirubin 0.8 mg/dL, and ALP-186 U/L]. Based on these, possible differentials were viral infection, post-acute COVID-19, steroid-induced immunosuppression, drug-induced liver injury (DILI) probably due to Pirfenidone, Multisystem Inflammatory Syndrome-Adult (MIS-A), or COVID-19 associated CSS. Biochemical analyses have been tabulated in Table 1. Serum serologies [for HIV 1 and 2, hepatitis A, B, C, D, and E, Epstein-Barr virus (EBV), parvovirus B19, herpes simplex virus (HSV), cytomegalovirus (CMV), dengue, HSV 1 and 2, VDRL, Rickettsia, Leptospira, and scrub typhus], peripheral blood smear for malarial antigens, and serum autoimmune profile (anti-nuclear antibodies via immunofluorescence assay) were sent.
Further investigations revealed an elevated serum lactate dehydrogenase (8918 U/L), serum D-dimer (> 5,000 ng/mL), serum ferritin (> 2,000 ng/ml), INR (1.6), and serum fibrinogen levels (128 mg/mL), indicating disseminated intravascular coagulation (DIC) - like picture with a probably viral, drug-induced (pirfenidone, steroids), or autoimmune etiology. Antimicrobials were changed empirically to intravenous piperacillin-tazobactam (4.5 g QID) and doxycycline (100 mg BD) with ursodeoxycholic acid (300 mg TDS). In light of persistent pancytopenia, a bone marrow biopsy was performed under cover of platelets transfusion. Ultrasonography of the whole abdomen revealed hepatomegaly.
On the second day, his dyspnoea worsened, and because of raised D-dimer, a CT pulmonary angiography of the chest was done to rule out post-COVID-19 pulmonary embolism. However, it showed only a consolidation in the left upper lobe and bilateral ground-glass opacities with no evidence of pulmonary embolism (Figures 1B,C). Furthermore, his troponin I and T were negative, with normal creatine phosphokinase (CPK) and N terminal pro-B-type natriuretic peptide (NT Pro-BNP) levels. A transthoracic 2D-ECHO was reported normal. On the third day, serum procalcitonin was raised (2.5 ng/mL), but the blood culture was sterile, and urine culture after 48 h of incubation showed Escherichia coli susceptible to colistin which was initiated. Persistent fever prompted us to send repeated blood cultures, fungal cultures, urine routine microscopy, and cultures for the next 3 days. Sputum induction failed as the patient had a dry cough. Meanwhile, all viral serologies were reported negative. The patient persistently had transaminitis [AST-11,000 U/L; ALT-12000 U/L; INR-1.6 (refer to Table 1, day-5)], with no bleeding manifestations or altered sensorium throughout his hospital stay. Empirically vitamin K, rifaximin, and lactulose were added to the treatment. Meanwhile, his serum beta-D glucan level, galactomannan level, and autoimmune profile, including anti-nuclear antibodies (ANA), p-ANCA, c-ANCA, and thyroid profile, were reported normal.
After correlating pancytopenia, hepatomegaly, and DIC, with a consistently raised serum ferritin (> 4,000 ng/ml), serum triglycerides (950 mg/dL) and reduced serum fibrinogen levels (< 150 mg/dL) with an ESR of 23 mm (during the first hour) with his clinical presentation, we contemplated the possibility of secondary HLH (Hemophagocytic lymphohistiocytosis) as part of CSS due to COVID-19 infection. Meanwhile, bone marrow biopsy showed a hypocellular marrow for his age (overall cellularity < 15%), with a possibility of aplastic anemia, malignancy, or an invasive pathology (Figure 1D). After correlating the clinical, biochemical, radiological, and bone marrow reports, we diagnosed sHLH based on the HLH 2004 criteria and an H-Score of 256 (Table 2A. Our patient fulfilled six of the eight HLH-2004 criteria points with an H-score of 256, indicating a 99% probability of having HLH (Table 2A).
The following etiologies for sHLH were considered: a post-COVID-19 infection, DILI due to pirfenidone, or sepsis-induced HLH (compounded by steroid-induced immunosuppresion). The close differentials were CSS and MIS-A. Nevertheless, autoimmune disease, tuberculosis, and other viral etiologies had been ruled out. Hence, as per HLH treatment protocol, intravenous injection of 10 mg dexamethasone two times a day with 30 g IVIG per day was started.
Furthermore, serum soluble interleukin-2 receptor (sCD25) levels and flow cytometry for immunodeficiency profile were sent. From day six to ten, our patient responded clinically to this treatment. Also, no fever was documented, and no new lung crepitations were heard on auscultation. Moreover, improvements in the biochemical profile and inflammatory markers were seen. Repeated blood, fungal, and urine cultures were reported to be sterile (Table 1, from day 6 to 9).
Later, his sCD25 levels were reported positive, and serum flow cytometry showed a reduction in the percentages of T cells (CD3: 9.21% vs. 53.2% control), B cells (CD19: 1.32% vs. 7.19% control), CD20 cells (1.06% vs. 7.29%), NK cells (CD 56: 0.13% vs 13.54% control), and CD15 (0.26% vs. 11.71% control), along with a reduced activity of NK cells, and yet the CD4:CD8 ratio was maintained. This report suggested humoral and cell-mediated immunosuppression in our patient along with low NK cell activity, which was consistent with the diagnosis of sHLH.
On the eleventh day, an erythematous, maculopapular rash developed, along with fever (101.7 F) episodes. It was a non-palpable rash measuring 0.5 to 1 cm, on the flexor and extensor aspects of both arms, hands, face, and upper abdomen, suggesting a non-vasculitic but infective etiology (Figure 2). Hence, intravenous teicoplanin was added to cover methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA) along with the antifungal fluconazole. He also had raised inflammatory markers [serum procalcitonin, lactate dehydrogenase (LDH), D-dimer, C-reactive protein (CRP), and interleukin 6 (IL-6)] with deranged kidney functions tests (refer to Table 1), which raised the possibility of sepsis due to a new hospital-acquired infection in an immunosuppressed state. Blood culture on day thirteen grew Candida auris, sensitive to caspofungin. Hence, fluconazole was replaced with caspofungin. His fever subsided, but on day fourteen, his kidney function tests further worsened, and he developed respiratory distress with worsening hypoxemic respiratory failure. His ECG and cardiac biomarkers were normal with a negative TruNat for SARS-CoV-2. A CT angiography of the chest was planned to rule out pulmonary embolism, as inflammatory markers along with d-dimer were raised, but the patient had to be intubated because of worsening respiratory distress. His repeat blood culture on day fourteen was again positive for Candida auris, suggesting disseminated Candidemia. He finally succumbed to his illness on day fifteen of hospitalization, despite our best efforts.
The final diagnosis in this case was post-COVID-19 sequelae with superadded pneumonia and sepsis leading to secondary HLH with opportunistic disseminated candidiasis, causing multi-organ failure [acute kidney injury (AKI) with acute respiratory distress syndrome (ARDS)]. Written consent was taken from the patient's relative for using clinical data for this case report.