CLINICOPATHOLOGICAL CORRELATION

https://doi.org/10.5005/jp-journals-11006-0078
Indian Journal of Critical Care Case Report
Volume 2 | Issue 5 | Year 2023

Double Trouble: Coronavirus Disease 2019 with Lupus Flare

Rashmi Joshi1https://orcid.org/0000-0003-1807-7674, Aravind Sekar2https://orcid.org/0000-0003-0196-3442, Aman Sharma3https://orcid.org/0000-0003-0813-1243, Sreedhara B Chaluvashetty4https://orcid.org/0000-0001-7526-2185, Mini P Singh5https://orcid.org/0000-0001-6263-1850, Amanjit Bal6https://orcid.org/0000-0002-1457-8589, Ritambhra Nada7https://orcid.org/0000-0002-8955-1428

1,2,6,7Department of Histopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

3Department of Internal Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

4Department of Radiodiagnosis and Imaging, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

5Department of Virology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

Corresponding Author: Aravind Sekar, Department of Histopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India, Phone: +91 8194896755, e-mail: aravindcmc88@gmail.com

Received on: 16 August 2023; Accepted on: 04 October 2023; Published on: 27 October 2023

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the coronavirus disease (COVID-19) pandemic, with over 65 million deaths worldwide. Clinical manifestations of COVID-19 varied from asymptomatic to severe acute respiratory distress syndrome. The exact incidence of COVID-19 in lupus patients is not known. However, studies have shown that lupus patients might be more prone to SARS-CoV-2 infection and may have severe clinical manifestations due to aberrant baseline inflammation and dysregulated immune responses. Further, the immunosuppressive treatment that lupus patients receive also compromises their immunity and paves the way for infection. We intend to present the complete clinical and autopsy findings of a 28-year-old female who presented with lupus flares involving major organs and acquired COVID-19 infection during treatment. Subsequently, there was worsening respiratory failure, and she finally succumbed to death despite all supportive measures.

How to cite this article: Joshi R, Sekar A, Sharma A, et al. Double Trouble: Coronavirus Disease 2019 with Lupus Flare. Indian J Crit Care Case Rep 2023;2(5):117–123.

Source of support: Nil

Conflict of interest: Dr Amanjit Bal is associated as the Section Editor (Clinicopathological Correlation) of this Journal and this manuscript was subjected to this Journal’s standard review procedures, with this peer review handled independently of this Section Editor and his research group.Patient consent statement: The author(s) have obtained written informed consent from the patient for publication of the case report details and related images.

Patient consent statement: The author(s) have obtained written informed consent from the patient for publication of the case report details and related images.

Keywords: Autopsy, Coronavirus disease 2019, Diffuse alveolar damage, Diffuse alveolar hemorrhage, Systemic lupus erythematosus

CASE DESCRIPTION

A 28-year-old female was admitted with a history of shortness of breath, orthopnea, palpitations, swelling of legs, and decreased urine output for 2 days. She was initially diagnosed with idiopathic thrombocytopenic purpura 6 years ago, and the diagnosis was subsequently revised to systemic lupus erythematosus (SLE) with renal and myocardial involvement 2 years back. A renal biopsy done at that time showed class III lupus nephritis with an activity score of 2/24 and a chronicity score of 0/12. The patient was noncompliant with therapy leading to two relapses before the current admission.

On general examination, she was anemic with bilateral pitting pedal edema; no cervical or axillary lymphadenopathy; blood pressure—180/100 mm Hg; pulse rate—125/minute; respiratory rate—30/minute; oxygen saturation of 96% on room air. Respiratory examination revealed bilateral basal crepitations and cardiovascular examination did not reveal any murmurs or added sounds. The abdomen examination revealed ascites with no palpable organomegaly. The neurological examination was normal. The laboratory investigations done during the hospital stay are shown in Table 1. Chest X-ray bilateral ill-defined nodular opacities, predominantly involving lower, and mid zones. Opacities were gradually increasing over time (Fig. 1).

Table 1: Different laboratory parameters during a hospital stay
Date 20/10/20 21/10/20 22/10/20 23/10/20 24/10/20 25/10/20 26/10/20 27/10/20 28/10/20
Hemoglobin (gm/dL) 6.7 8.4 7.2 7.0 6.8 5.7 6.8 6.4 6.4
Platelet (*103 cells/mm) 74 63 67 35 46 30 85 1,09 76
TLC (*103 cells/mm) 13.9 17.0 17.2 10.7 9.9 10.1 17600 12900
Na/K (mEq/L) 138/ 7.7 140/ 5.8 140/ 5.9 140/5 140/4.9 143/4.5 131/4.0 135/5.4 136/4
Urea/creatinine (mg/dL) 136/ 3.46 104/2.76 101/2.75 83/2.7 111/3.02 146/3.3 131/4.1 193/3.97 118/2.96
SGOT/SGPT (U/L) 33/19 15/14 16/20 14/22 21/23
Bilirubin total/direct (mg/dL) 0.2/0.1 0.1/0.08 0.3/0.1 00.2/0.16
Ca/P (mg/dL) 7/10.9 6.9/11.68 8.7/6.5
Protein/albumin (mg/dL) 4.8/1.92 3.8/1.86 3.8/1.91 3.8/1.7 4.7/2.1 4.5/2.01
Ferritin (ng/mL)/procalcitonin (ng/mL) 1913/6.5 1496/– 1496/6.4 1347/100 1261/–
CRP (mg/dL)/LDH (U/L) 52/– 50/– 42/540 63.1/531
ProBNP (pg/mL)/trop T (ng/mL) 30367/70 25354/51 26205/55 24614/74.2 37028/66
PT/PTI/aPTT (seconds) 13/98/30 12/100/30 13/98/32 13/92/1.1 12/100/118 22/58/106
Fibrinogen (gm/dL) 6.02 6.16 6.12 5.33
D-dimers (ng/mL) 1423 4867 3899
Blood and urine culture Sterile

TLC, total leukocyte count; Na/K, sodium/potassium; SGOT, serum glutamic oxaloacetic transaminase (Aspartate aminotransferase); SGPT, serum glutamic pyruvic transaminase (Alanine aminotransferase); CRP, C-reactive protein; LDH, lactate dehydrogenase; ProBNP, Pro-B-Type natriuretic pepetide

Fig. 1: Serial chest X-rays showing ill-defined nodular/alveolar opacities predominantly involving bilateral lower and mid zones of lungs

A possibility of lupus flare in the form of lupus nephritis and myocarditis was considered. She received one session of hemodialysis for hyperkalemia and severe metabolic acidosis. Her nasopharyngeal sample was subjected to SARS-CoV-2. Gene Xpert came, which turned out to be positive. She was shifted to the coronavirus disease (COVID-19) intensive care unit (ICU) and was put on noninvasive ventilation for respiratory failure. There was a progressive deterioration of cardiac function. Injection piperacillin, tazobactam, dexamethasone, and subsequently methylprednisolone 125 mg and intravenous immunoglobulin (Ig) were given during ICU admission. She was intubated due to worsening respiratory failure and put on mechanical ventilation. Injections of methylprednisolone 500 mg/day and rituximab 500 mg were given. There was progressively worsening hypotension requiring increasing inotropic support. Injection colistin was added due to suspicion of sepsis. Preterminal, she developed profuse bleeding from the endotracheal (ET) tube. She developed the first cardiac arrest from which she was revived but continued to worsen further and developed a second cardiac arrest after some time. Despite all supportive measures, her vitals continued to deteriorate, and she went into asystole. The resuscitation was unsuccessful, and she could not be revived. Almost 2 days before the demise, the nasopharyngeal swab was again tested for SARS-CoV-2 by real-time polymerase chain reaction (RT-PCR) using an Indian Council of Medical Research-approved kit as per the manufacturer’s instructions and was reported negative (Flowchart 1).

Flowchart 1: The database of the case is shown in the flowchart

CLINICAL DISCUSSION

Dr Aman Sharma

Basic Disease

Clinical, laboratory, and biopsy findings of the patient fulfill the diagnosis of SLE as per both the systemic lupus international collaborating clinics classification criteria and the new American College of Rheumatology/European League Against Rheumatism criteria. She was Started on intravenous pulses of cyclophosphamide (euro lupus regimen) and received six pulses; her last dose was on 13/3/20. She was lost to follow-up and did not take any maintenance therapy. After 1 year, she presented with renal and hematological flare.

Coronavirus Disease (COVID-19)

Coronavirus disease (COVID-19) RT-PCR done during the current admission was positive and turned out to be after 5 days.

The Extent of Involvement:

At current admission, the patient had respiratory failure, renal failure, hematological manifestations, and myocarditis.

Causes of Respiratory Failure:

Breathlessness and respiratory failure might occur due to COVID-19 pneumonia or diffuse alveolar hemorrhage (DAH) caused by SLE.

  • Epidemic setting, COVID-19 RT-PCR positivity favors the possibility of COVID-19 pneumonia, but the patient had no fever at the onset, and PCR turned out to be negative on day 5.

  • Fall in hemoglobin levels for which multiple transfusions were required; preterminal ET bleed and the disease activity in other organs favor the possibility of DAH.

Causes of Renal Failure:

  • An increase in creatinine, low C3, and systemic flares with other organ involvement, such as joint pains and myocarditis, favor the strong possibility of progression to class IV lupus nephritis.

  • Thrombotic microangiopathy (TMA) occurring in the setting of SLE, and antiphospholipid antibody syndrome might also be considered one possibility for renal failure.

  • Renal failure can also occur in COVID-19 infection. Collapsing glomerulopathy, TMA, and acute tubular injury were the causes described in the literature.

Hematological Manifestation:

There was a progressive fall in hemoglobin levels. Although there was a documented history of iron deficiency, the iron profile was normal in the current admission. There was no evidence of microangiopathic hemolytic anemia at the peripheral smear, and the direct Coombs test was normal. Preterminal ET bleeds strongly suggest the possibility of DAH.

Can it be Catastrophic Antiphospholipid Antibody Syndrome?

Involvement of more than three organs and development of manifestations in <1 week. The index case qualifies for the diagnostic criteria for antiphospholipid antibody syndrome. However, histological evidence and laboratory documentation of antiphospholipid antibodies were not available in this case.

Terminal Events

Septic shock and disseminated intravascular coagulation (DIC) might be the terminal event. COVID-19 infection can also be associated with coagulopathy. COVID-19-associated coagulopathy appears to be distinct from DIC due to elevated fibrinogen, modest prolongation of the activated partial thromboplastin time, and the absence of schistocytes in the blood film.

Chairperson (Dr Sanjay Jain): Thank you, Dr Aman Sharma, for the excellent clinical demonstration and discussion of the case. What could be the causes of a lupus flare? Can virus infection trigger lupus flare?

Dr Aman Sharma: Lupus flares can occur in 20–25% of SLE patients within 1–2 years and 40–66% within 5–10 years after achieving clinical remission.1,2 The risk factors for flare are African American race, male gender, age of SLE onset ≤25 years, significant organ involvement (such as cytopenia, neuropsychiatric lupus, nephritis, and vasculitis), persistent clinical disease activity, immunological activity, (low serum C3/C4, high anti-double-stranded DNA) and poor compliance to treatment.3 Viral infection can also trigger factor lupus.4 The index case had a previous history of two flares due to poor compliance with treatment. However, the current flare-up was associated with COVID-19.

The incidence of COVID-19 in lupus varies between 2 and 4%, though the exact occurrence is unknown due to the limited availability of RT-PCR testing and the inclusion of only severely ill patients in most studies.5 The facts such as aberrant T cell-mediated immunity, increased baseline inflammation, augmented ACE expression in SLE patients, and further long-term immunosuppressive medications make them vulnerable to SARS-CoV-2 and severe clinical course once acquired.

In this case, rapid clinical deterioration occurred due to lupus flare as evidenced by laboratory investigations and further complicated by COVID-19.

Audience 1: What could be the cause of lymphopenia in this patient?

Dr Aman Sharma: The patient was on immunosuppression for a long duration, which itself can cause lymphoid depletion. Absolute lymphopenia observed in this case can also be due to COVID-19 or lupus flare because of a cytokine storm.6

Autopsy findings: A complete autopsy was performed with a bitemporal and midline thoracoabdominal incision with due consent from the deceased relatives. On the opening of the serous cavities, the peritoneal cavity yielded 1500 mL of straw-colored fluid; the pericardial cavity yielded 30 mL of blood-tinged fluid; pleural cavities were within the standard limit. Both lungs were markedly heavy and weighed 1,020 gm [reference range (RR), 550–650 gm]. The pleural surface showed a prominent mosaic-like pattern (Fig. 2A). The cut surface of both lungs was firm to feel and showed discrete and confluent hemorrhagic areas with pale, firm areas in between (Fig. 2B). There was no thrombus in the pulmonary arteries and their branches. Microscopic examination of sections from the nonhemorrhagic portion of the lungs showed markedly thickened interalveolar septa due to edema and infiltration by leukocytes (Fig. 3A); hyaline membrane lining most of the alveolar wall (Fig. 3B); pulmonary edema and foci of bronchopneumonia; fibrin balls in few alveolar spaces (Fig. 3C); marked type II pneumocyte hyperplasia with reactive atypia and syncytium formation (Fig. 3D); desquamation of pneumocytes; thick inspissated mucous secretion in lobar and many segmental bronchi (Fig. 3E). On immunohistochemistry with SARS-CoV-2 nucleocapsid antibody, viral particles in the cytoplasm of shed-out type II pneumocytes were highlighted (Fig. 3F). Sections from the hemorrhagic areas showed bland hemorrhage, distending the alveoli without any capillarities (Fig. 3G). On immunofluorescence (IF), capillaries in the interalveolar septa showed 2+ intense deposits for IgG and C4d (Fig. 3H).

Fig. 2: The pleural surface of both lungs shows a prominent mosaic-like pattern; (B) Cut surface of the lung shows pale firm areas along with discrete and confluent foci of hemorrhages

Fig. 3: A to H: Photomicrograph of the lung: (A) Marked widening of interalveolar septa with edema and inflammatory cell infiltrate and areas of alveolar hemorrhage (hematoxylin and eosin, 100×); (B) Refractile hyaline membrane lining alveolar wall indicative exudative phase of DAD (hematoxylin and eosin, 200×); (C) Fibrin ball in few alveolar spaces (hematoxylin and eosin, 100×); (D) Marked type II pneumocyte hyperplasia, desquamation of pneumocytes and significant trapping of megakaryocytes in pulmonary capillaries (hematoxylin and eosin, 200×); (E) Bronchioles are plugged with thick inspissated mucus secretion (hematoxylin and eosin, 200×); (F) Immunohistochemistry with SARS-CoV-2 nucleocapsid antibody highlighting viral particles in the cytoplasm of shed out type II pneumocytes; (G) Alveolar spaces are distended with hemorrhage and not associated with capillarities (hematoxylin and eosin, 200×); (H) Direct IF for IgG showing 3+ intense positivity along the capillary wall in the interalveolar septa (FITC, 200×)

Both kidneys weighed 520 gm (RR, 160–320 gm), and the capsular surface showed irregular petechiae and tiny hemorrhagic spots (Fig. 4A). There was no focal lesion on the cut surface. Microscopic examination showed crescents of different ages in 70% of total glomeruli and variable degrees of endocapillary hypercellularity, wire loop lesions, hyaline thrombi, and neutrophilic infiltration in the underlying tuft (Fig. 4B). In addition, >50% of glomeruli showed global thickening of the basement membrane (Fig. 4C). Mesangiolysis with congested capillary loops were seen in a few glomeruli (Fig. 4D). The IF showed a full house pattern with moderate to marked intense coarse granular positivity for all Ig and complements in the mesangium and along the glomerular capillary wall. As per the International Society of Nephrology/Renal Pathology Society classification, class IV + V with an activity index score of 12/24 and chronicity index score of 4/12 was assigned.

Fig. 4: Gross view of kidneys showing irregular petechial hemorrhages on the capsular surface; (B) Histological examination showing fibrocellular crescent with rupture of Bowman capsule and lobular accentuation due to endocapillary hypercellularity in one glomerulus and wire loop lesion along with hyaline thrombi in another glomerulus (hematoxylin and eosin, 200×); (C) Global thickening of basement membrane and stiff capillary loops along with wire loop lesion (Periodic acid–Schiff, 200×); (D) Glomerulus showing marked mesangiolysis and congestion (paralyzed glomerulus) (Periodic acid–Schiff, 200×)

The heart weighed 330 gm (RR; 233–383 gm), and the pericardial surface showed a fibrous plaque lesion. All chambers and valves were within the normal limit. Coronaries were dissected and did not show a thrombus. Microscopic examination of the myocardium showed features of myocarditis such as disarray in the arrangement of myofibers with degenerative changes in some of them, marked edema, and lymphomononuclear cell inflammation in the interstitium (Fig. 5A). Pericardium showed fibrosis with scant inflammatory cells. On IF, 2+ intense deposits for IgG were noted in both pericardial and myocardial arterioles. Few myocytes also showed deposits for IgG (Fig. 5B).

Fig. 5: Photomicrograph of midbrain showing microhemorrhage (hematoxylin and eosin, 200×); (B) Direct immunofluorescence (DIF) showing IgG deposits in one of the capillaries (FITC, 200×); (C) Photomicrograph of the heart showing disarray and degenerative changes in myofibers; marked interstitial edema and sparse lymphomononuclear cell inflammation (hematoxylin and eosin, 200×); (D) DIF showing IgG deposits in one of the myocardial vessels (FITC, 200×); (E) Lymph node showing marked hemophagolymphoshistiocytosis (hematoxylin and eosin, 200×); (F) Spleen showing marked white pulp depletion and congested red pulp (hematoxylin and eosin, 200×)

The brain weighed 1,213 gm (RR; 1,200–1,400 gm). Grossly no changes were observed on the outer and cut surface. However, the microscopic examination showed foci of microhemorrhages in the pons and midbrain with 2+ intense deposits for IgG in arterioles on IF (Figs 5C and D). The lymph node shows a marked depletion of follicles, sinus histiocytes, and florid hemophagolympohisitocytosis (Fig. 5E). The liver weighed 1,500 gm (RR; 1,200 gm) and grossly and microscopically was unremarkable. Spleen weighed 450 gm (RR; 120 gm) and enlarged. Histological examination of the spleen showed marked attenuation of white pulp with depletion of B and T cells in their zones (Fig 5F). Bone marrow showed an adequate representation of erythroid, myeloid, and megakaryocytic lineage elements. Small and large intestines showed organizing serositis. The uterus showed foci of adenomyosis. Skeletal muscle, adrenal, and thyroid glands were unremarkable.

Fresh tissue of the lung, kidney, spleen, and formalin-fixed tissue of the heart, small intestine, and lymph node were subjected to RT-PCR for COVID-19. This was found to be positive in the lung and splenic tissue, whereas the heart, kidney, small intestine, and lymph node were negative.

Final Autopsy Diagnosis

In this 28-year-old female known case of SLE—relapse and COVID-19 RT-PCR positive.

Features of SLE in the form of:

  • Lupus nephritis class IV + V with uncomplicated vascular immune deposits (activity 12/24 and chronicity 4/12).

  • Diffuse alveolar hemorrhage (DAH) with IgG and C4d deposits in capillaries (lupus pneumonitis).

  • Lupus myocarditis and pericarditis.

  • Lupus vasculopathy with microhemorrhage in midbrain and pons.

  • Diffuse alveolar damage (DAD), exudative phase (in transition state) with RT-PCR positive for SARS-CoV-2.

  • Hemophagolymphohistiocytosis.

  • Marked lymphoid depletion in the lymph nodes and spleen (RT-PCR positive for SARS-CoV-2).

DISCUSSION

ORCID

Rashmi Joshi https://orcid.org/0000-0003-1807-7674

Aravind Sekar https://orcid.org/0000-0003-0196-3442

Aman Sharma https://orcid.org/0000-0003-0813-1243

Sreedhara B Chaluvashetty https://orcid.org/0000-0001-7526-2185

Mini P Singh https://orcid.org/0000-0001-6263-1850

Amanjit Bal https://orcid.org/0000-0002-1457-8589

Ritambhra Nada https://orcid.org/0000-0002-8955-1428

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