Acute Respiratory Distress Syndrome in a Carrier of an Interleukin-36 Receptor Antagonist Mutation With Generalized Pustular Psoriasis

Abstract

Background

Generalized pustular psoriasis of von Zumbusch is a rare variant of psoriasis often accompanied by systemic, sometimes life-threatening, symptoms. Generalized pustular psoriasis sometimes arises in pregnancy.

Case report

A 31-year-old female, with a history of schizophrenia and recurrent episodes of gestation-associated pustular psoriasis, was admitted to our department because of a generalized pustular rash during the 22nd week of her fifth pregnancy. Clinical and histopathological examinations were suggestive of generalized pustular psoriasis (von Zumbusch type). During this hospitalization, she developed acute dyspnea, fever, tachycardia, and marked leukocytosis. An extensive workup failed to reveal an infectious, cardiac, or pulmonary abnormality, while severe respiratory distress necessitated mechanical ventilation. Radio-imaging revealed diffuse alveolar infiltrates consistent with acute respiratory distress syndrome (ARDS). In the absence of any other plausible cause, ARDS was considered as secondary to her skin disease. Genetic base was suspected, and genetic analysis uncovered a novel mutation in IL36RN encoding the IL-36 receptor antagonist. Only 15 cases of ARDS secondary to psoriasis have been described to date. This is the first report of this very rare complication in a known carrier of an IL36RN mutation. The fact that IL36RN is abundantly expressed in the lung as well as in the epidermis may underlie the unusual clinical features of this dramatic case.

Conclusion

The present case suggests the need to carefully monitor patients with pregnancy-associated generalized pustular psoriasis for possible life-threatening pulmonary complications and the possible link to IL36RN mutation.

Introduction

Generalized pustular psoriasis (GPP) of von Zumbusch is a rare variant of psoriasis often accompanied by systemic, sometimes life-threatening, symptoms. GPP sometimes arises in pregnancy, a condition previously known as impetigo herpetiformis, a denomination that is no longer accurate and is referred nowadays as GPP in pregnancy. ¹ The molecular basis of GPP had been uncovered over the last years, as the disease was associated with mutations in the gene coding for IL-36 receptor antagonist (IL36RN). ²

Case Report

A 31-year-old female, with medical history notable for schizophrenia, was diagnosed with mild plaque–type psoriasis at 15 years of age. Six years later, recurrent episodes of generalized pustular eruption appeared, requiring multiple hospitalizations. Overall, more than 10 flares have been recorded over the course of a decade, 5 of which appeared during pregnancy, while others co-occurred after infection (pharyngitis) or medication use (amoxicillin). During these episodes, the patient presented with near erythroderma with multiple pinhead non-follicular pustules, coalescing to form small lakes of pus (Figure 1). Biopsy showed epidermal neutrophilic infiltrate and intra-epidermal pustules (Figure 2). The recurrent flares were accompanied by fever, chills, tachycardia, leukocytosis, elevated CRP, and anemia that required blood transfusions on several occasions. In addition, our patient reported fetal death, which occurred during her second pregnancy, at 35^th week of gestation while she was experiencing a flare of her skin disease.

Figure 1.

Well-demarcated erythematous plaques with pinhead pustules coalescing to form small lakes of pus.

Figure 2.

Epidermal neutrophilic infiltrate and intra-epidermal pustules compatible with pustular psoriasis.

On November 2013, during her fifth pregnancy, at 22 weeks of gestation, she developed tachypnea up to 40 breaths per minute accompanied by fever of 38°C and sinus tachycardia of up to 140 beats per minute. Initially, chest radiograph was unremarkable, and the dyspnea subsided in response to treatment with antibiotics, furosemide, and low–molecular weight heparin, as pulmonary embolism or sepsis were initially suspected. A thorough workup including recurrent blood and urine cultures, chest X-rays, and an echocardiogram ruled out these diagnoses. Four weeks afterward, at 26 weeks of gestation, she developed another dyspneic episode that did not respond to medication or continuous positive airway pressure ventilation. Promptly, intubation was performed with subsequent mechanical ventilation. The laboratory was notable for leukocytosis (27,000 10⁹/L) with relative neutrophilia of 96% and anemia (hemoglobin = 8.6 g/dL). Chest X-rays showed diffuse infiltrates that supported a diagnosis of acute respiratory distress syndrome (Figure 3) and the patient was diagnosed with ARDS, according the Berlin definition criteria. ³ Although a viral upper respiratory infection as a trigger to the flare cannot be ruled out, a thorough workup including negative viral serology and repetitive negative blood and urine cultures did not reveal any infection. An echocardiogram with preserved left ventricular function ruled out a cardiac or thromboembolic etiology. Accordingly, she was treated with high-dose methylprednisolone at a dose of 0.5 g/day for 3 days and with cyclosporine at a dose of 3 mg/kg as well as tazobactam, clindamycin, and vancomycin with resolution of the respiratory distress. In the following days, she suffered from marked tachycardia. Holter testing showed inappropriate sinus tachycardia with a peak pulse of 175 beats per minute, and echocardiograms showed a decrease in ejection fraction (down to 40%) and diastolic dysfunction grade 2 (Figure 4). As no evidence of anemia, thyroid function abnormality or infectious disease was obtained, and high throughput heart failure was diagnosed. She was treated successfully with verapamil, and eventually cardiac function returned to normal. At 32 weeks of gestation, due to fetal distress, a premature but healthy baby was delivered through C-section.

Figure 3.

Chest X-ray reveals diffuse alveolar infiltrates.

Figure 4.

Left ventricular function according to segments demonstrating systolic dysfunction with hypokinesis and akinesis in all segments.

The protracted disease course and multiple GPP flares led us to suspect the existence of an underlying genetic defect. Using Sanger sequencing, we identified a heterozygous change in the IL36RN gene (c.244-1 G>C) (Figure 5). This change is not found in gnomAD (https://gnomad.broadinstitute.org/gene/ENSG00000136695) and is predicted to compromise normal mRNA splicing (http://www.fruitfly.org/seq_tools/splice.html & SpliceAI—0.97). The mutation was predicted to be “high” for “MSC_CADD Impact_Pred” with a 99% confidence interval and CADD score of 33. We were unable to obtain an RNA sample from the patient to validate this prediction.

Figure 5.

Direct sequencing of IL36RN revealed a heterozygous G>C transversion (arrow) at position c.244-1 of the cDNA sequence in the patient (upper panel). The wild-type sequences (WT/WT) are given for comparison (lower panel).

Discussion

We report a case of GPP associated with a spectrum of severe complications: anemia, stillbirth, heart failure, and ARDS. To date, to our knowledge, there have been 15 reported cases of GPP or psoriatic erythroderma complicated with ARDS.^4-6 Our patient was treated with methotrexate in the year preceding the respiratory event, but the patient ceased receiving this medication several months prior to this event due to her anticipated pregnancy. Moreover, a normal baseline chest X-ray and absence of circulating eosinophilia make methotrexate hypersensitivity quite unlikely in this setting.

Fetal distress, preterm labor, and abortion are documented complications of GPP^7,8 and until recently, were attributed to the general inflammatory burden of the disease. Placental expression of IL36RN, may suggest a molecular explanation for these complications in our patient. Tachycardia and heart failure are known systemic manifestations of GPP. As both high-output cardiac failure and peripartum cardiomyopathy display overlapping manifestations, the latter cannot be ruled out.

We report a novel mutation in IL36RN which is predicted to result in aberrant splicing of exon 5. As a rule, the disease follows Mendelian transmission, and as the mutation is heterozygous, a search for a second IL36RN mutation in the whole coding region of the gene including non-coding margins of the axons did not reveal another mutation. Yet, the possibility of an unidentified mutation, or a mutation in a non-coding region, cannot be excluded. To our knowledge, there are only 9 reported cases of mutations of this gene in patients with GPP in pregnancy,^2,9 supporting the assumption that this entity is a variant of GPP. Aside from the skin and placenta, expression of IL36RN was found in the lung, ¹⁰ which may possibly underlie pulmonary complications in GPP, such as ARDS. It is possible that milder respiratory symptoms in the context of GPP are more frequent than usually thought. Unveiling the genetic basis of the disease enables consideration of not only traditional therapies, as cyclosporine in our case, or anti-TNF inhibitors and other biologics, but also targeted therapies such as IL-1 inhibitors, and even specific IL-36 agents, that are presently studied. ¹¹

In summary, the present case suggests the need to carefully monitor patients with pregnancy-associated GPP for possible life-threatening pulmonary complications.

ORCID iD

Efrat Bar-Ilan https://orcid.org/0000-0003-1260-3960