Rare presentation of rare disease: Idiopathic inflammatory myositis presenting initially as acute respiratory distress syndrome

Sir,

Idiopathic inflammatory myositis is a group of heterogenous connective tissue diseases that mostly affect skeletal muscles and also involve other organ system. The most common extra-muscular target is the lungs. Pulmonary involvement is usually an interstitial lung disease (ILD), which may often present with an inaugural manifestation as an acute respiratory failure or as an acute exacerbation of chronic ILD. Idiopathic Inflammatory Myopathies (IIM)-associated ILD (IIM-ILD) contributes to nearly 80% of the mortality in IIM, with a reported prevalence of 65% of newly diagnosed IIM cases.[1,2] Acute Respiratory Distress Syndrome (ARDS), presenting as the inaugural manifestation of ILD, is the most challenging. Early diagnosis is crucial to prevent mortality. Early initiation of appropriate specific treatment, such as corticosteroids or immunosuppressants (MMFs), along with optimal ventilator settings, improves the outcome in IIM-associated ILD presenting as acute respiratory failure.

Based on clinical, immunological and histological features, IIM can be differentiated into five groups. (i) Overlap myositis, which is the most common; (ii) Dermatomyositis; (iii) Immune-mediated necrotizing myopathy; (iv) Sporadic inclusion body myositis; (v) Polymyositis. ILD commonly occurs in overlap myositis, among which anti-synthetase syndrome is the most frequent.

The current classification of inflammatory myopathies and the respective autoantibodies includes ILD due to acute respiratory failure (ARS), anti-tRNA-ant synthetase autoantibodies, including anti-Jo-1 (anti-histidyl transfer RNA synthetase), PL7 (anti-threonyl t-RNA synthetase antibody), PL12, OJ, EJ, Zo, KS, and YRS. NXP2: example of a myositis-specific autoantibody or a myositis-associated autoantibody; when appearing inside grey circles, the autoantibodies have been shown to correlate with the occurrence of either ILD or cancer, respectively [Figure 1].[3]

Figure 1.

Current classification of inflammatory myopathies and the respective autoantibodies. ILD, Interstitial Lung Disease; ARS, anti-tRNA-anti synthetase autoantibodies, including anti-Jo-1, PL7, PL12, OJ, EJ, Zo, KS, YRS. NXP2

ARDS has been defined using Berlin criteria.[4] PaO2/FiO2 between 201 and 300 mmHg is defined mild ARDS, 101 and 200 mmHg moderate ARDS and PaO2/FiO2 less than or equal to 100 mmHg severe ARDS; these PaO2/FiO2 values were with a Positive End Expiratory Pressure (PEEP) level of at least 5-cm H2O. We present our experience of patients with myositis presenting initially as ARDS.

This was a retrospective observational case series. The study included patients presenting with fever, dry cough and breathlessness and acute respiratory failure and who were admitted to the respiratory ICU of our hospital [Table 1]. These patients required high-flow oxygen or non-invasive ventilation on admission without prior cardiac and pulmonary comorbidities, including ILD. The severity and diagnostic evaluation parameters are depicted in Table 2. All patients were initially managed as cases of acute interstitial pneumonia with broad-spectrum parenteral antibiotics, non-invasive ventilation and supportive care. Aetiological evaluation for common viral, bacterial and parasitic infections was performed for all patients. Nasal and oropharyngeal swab reverse transcription-polymerase chain reaction test was done for COVID-19 (Coronavirus disease), H1N1 and other common respiratory viruses, which was negative. Paired blood pyogenic culture on seventh day and urine pyogenic culture on third day showed no growth; serum procalcitonin levels of all patients were negative (<0.5 ng/ml). Common tropical infection, peripheral blood smear for malarial parasites and dengue serology were negative.

Table 1.

Main Characteristics of the 04 study patients at ICU admission

	Median or n (%)
Demographics
Age in years	58 (42-63)
Sex	Female, 4 (100%)
Comorbidities	Obesity-1 (25%): Hypertension-1 (25%)
Biomass fuel exposure	3 (75%)
Exposure to pneumotoxic drugs	Nil
Occupational exposure	Nil
Clinical Presentation
Days from respiratory symptom onset to admission	4 (2-6)
Skin rash	Nil
Arthralgia	Nil
Clubbing	Nil
Bilateral Pedal Edema	Nil
JVP	Not raised
Crackles	4 (100%)

Table 2.

Severity diagnostic evaluation parameters of the patients

	Median or n (%)
Criteria for ARDS*
P/F ratio	89.5 (76-132)
Ventilatory support
Non-invasive ventilation	4 (100%)
High flow oxygen	4 (100%)
Chest radiograph
Alveolar opacities	4 (100%)
Pleural effusion	Nil
HRCT chest
Diffuse Ground Glass opacities	4 (100%)
Inter lobular septal thickening	4 (100%)
Fibrosis (traction bronchiectasis and/or honeycombing)	Nil
consolidation	Nil
Pleural effusion	Nil
Serological
CPK (U/L)	53.5 (38-149)
LDH (IU/L)	572 (433-750)
CRP (mg/l)	155.5 (76-246)
ANA by IF
nuclear/nucleolar pattern	1+ (75%), 2+ (25%)
Anti CCP	Negative
S. Aldolase (u/l)	17 (11-22)
ENA panel	Negative
Myositis panel
Mi-2	2 (50%)
Pl-7	2 (50%)
TIF1- Y	1 (25%)
Jo-1	Negative

A careful clinical examination was performed to look for features of an underlying connective tissue disorder and left heart failure. None of the patients had clinical features suggestive of an underlying rheumatic disorder except for proximal muscle weakness of both lower limbs. All patients’ inflammatory markers lactate dehydrogenase (LDH) (>190 IU/L) and quantitative C-reactive protein (CRP) (>5 mg/l) were significantly raised, along with computed tomography suggestive of an NSIP pattern, in view of which all patients were further evaluated for connective tissue disorder. ANA by immunofluorescence method was done, which was positive in patients with nuclear/nucleolar pattern 1+ (75%) and 2+(25%). Extractable nuclear antigen (ENA) profile was performed and was negative in all patients. The additional test for serum muscle enzyme creatinine phosphokinase (CPK), aldolase was performed along with a myositis profile by the immunoblot method. Table 1 shows the main characteristics of patients at the time of their admission to the ICU.

RESULTS

All the patients had severe hypoxemia and bilateral diffuse pulmonary infiltrates on the chest radiograph. Table 1 lists the main baseline characteristics of all patients on admission. All patients were female. The Berlin criteria for ARDS were met in all patients; three (75%) had severe ARDS and one (25%) had moderate ARDS. None of the patients had any characteristic clinical features of a connective tissue disorder. Table 2 elaborates on the diagnostic evaluation. HRCT chest showed predominantly ground glass opacities without any evidence of fibrosis in all patients [Figure 2]. All patients had significantly raised inflammatory markers, and ANA by immunofluorescence was positive in all patients; however, the ENA panel, including (Jo-1), was negative. CPK was not raised in three patients (<145 U/l) and minimally raised in one patient (148U/l). Serum aldolase was significantly raised in all patients (>7.5 u/L). In the myositis profile, Mi-2 was positive in two patients (50%), Pl-7 in two patients (50%) and TIF-1Y was positive in one patient (25%). In all patients (n = 4), Magnetic Resonance Imaging (MRI) of both thighs showed diffuse STIR hyperintensity in vast groups of muscles along with oedema in intermuscular planes, findings consistent with myositis. The classification of patients was done using the EULAR ACR criteria [Table 3]. When we derive the score of all patients (n = 4) as per the EULAR/ACR classification criteria for adult or juvenile IIM, all our patients have a score of 5.8. (Predetermined cut-off ≥5.5 <7.5 without muscle biopsy for probable IIM).[5]

Figure 2.

(a) chest radiograph bilateral ill-defined air space opacities in mid and lower zones. (b) high-resolution computed tomography of the chest showing bilateral NSIP pattern

Table 3.

Clinical and lab parameter scores of the patient as per the EULAR/ACR classification criteria[5]

Variable	Score Points
	Without muscle biopsy	n (%)
Age of onset ≥40 years	2.1	4 (100%)
Objective symmetric weakness proximal upper extremities	0.7	4 (100%)
Objective symmetric weakness proximal lower extremities	0.8	4 (100%)
In the legs, proximal muscles are relatively weaker than distal muscles	0.9	4 (100%)
Anti-Jo-1 (anti-histidyl-tRNA synthetase) autoantibody present	3.9	0
Elevated serum levels of creatine kinase (CK) or lactate dehydrogenase (LDH) or aspartate aminotransferase (ASAT/AST/SGOT) or alanine aminotransferase (ALAT/ALT/SGPT)	1.3	4 (100%)
Total score	5.8 (n=4)

All patients were initially managed with non-invasive ventilation followed by a high-flow nasal cannula. Table 4 elaborates on the management outcome of the patients. All patients were managed with high-dose steroids (methylprednisolone) for 3 days, then gradual tapering of the dose with an addition of an MMF. The median time for liberation from NIV was 3 days, dose of Methyprednisolone as 500mg and weaned off from supplemental oxygen was 25 days. All patients were able to stand from a squatting position, which reflects a significant improvement in the strength of the proximal muscles of both lower limbs on median of 7 days. We performed a malignancy screening Computed Tomography (CT) scan of the chest, abdomen and pelvis of all patients. One patient with TIF-1γ- positivity was found to have a gastrointestinal stromal tumour (GIST).

Table 4.

Management and outcome

	Median or n (%)
Ventilatory support
Non-invasive ventilation	4 (100%)
Treatments
Antibiotics	4 (100%)
High dose steroids	4 (100%)
Outcome
Duration of non-invasive ventilation (days)	3 (2-5)
Duration of supplemental oxygen requirement (days)	25 (21-28)
Improvement in lower limbs proximal muscle strength	7 (5-10)

DISCUSSION

In patients presenting with ARDS without any prior history of DPLD, establishing a diagnosis of ILD is a major challenge. Crackles on auscultation and diffuse pulmonary infiltrates on chest radiographs are non-specific signs that do not differentiate ILD from other causes of ARDS. High-resolution CT is a sensitive diagnostic tool for diagnosing and classifying ILD based on various CT patterns.[6] Various studies have reported ILD as the initial clinical presentation, which precedes the manifestation of myopathy, which ranges from 7.2% to 37.5%.[7,8,9] The validated EULAR/ACR classification criteria do not include ILD in its classification, even though most of the patients with IIM present to the hospital with respiratory symptoms and ILD being a major cause of hospitalization, various studies have reported mortality rate that ranges from 7.5% to 44%.[5,10,11,12,13] Anti-histidyl tRNA synthetase antibody, often referred to as anti–Jo-1 antibody, is the most frequently detected anti-synthetase autoantibody, comprising up to 60% of all aminoacyl-t RNA synthetase enzyme (ARS-Abs), and is strongly associated with the presence of ILD in both PM and DM.[14,15,16] Anti-Jo1 is well described in the literature; however, other myositis-specific antibodies like Anti PL-12, Anti PL-7 and Anti KS appear to be associated with isolated ILD, and the diagnosis of ILD precedes the manifestation of myositis.[16,17] When compared to anti-Jo 1, lung involvement is more frequent and severe in both anti-PL-12 and anti-PL-7.[18,19] Anti-Ku and anti-PM- Scl antibodies, which are most commonly present in overlap myositis, are also associated with ILD.[20,21] The validated EULAR/ACR classification criteria for IIM only include anti-Jo 1, but it did not allocate score points for other non-Jo 1 myositis-specific or myositis-associated antibodies and also did not integrate ILD into its classification system, which is one of its drawbacks. The literature on other myositis-specific and myositis-associated antibodies is sparse. In our study, all patients were female, and the anti-Jo-1 antibody was negative in all of them. Mariampillai et al. in their study sorted IIM into four major clusters and reported pulmonary involvement in every patient. They proposed a new classification system for IIM based on clinical findings and the inclusion of extended myositis-specific antibodies (MSA) panel. In their study, they concluded that MSA should be incorporated into the classification of IIM, which seemed to be more beneficial than the morphologic features obtained on histopathologic examination of a muscle biopsy.[22] The spectrum of IIM-ILD ranges from asymptomatic basilar lung fibrosis to an acute, rapidly progressive condition associated with ARDS and respiratory failure.[23,24] IIM can present with lung involvement alone without rheumatologic features, and IIM-associated ILD has a prevalence of 78% in IIM and often has devastating clinical manifestation.[2] Inflammatory myositis is often considered a paraneoplastic process. Hill et al.[25] in their study reported a cancer rate of 32% in 618 DM cases and 15% in 914 PM cases. A meta-analysis by Lega et al.[26] demonstrated the prevalence of cancer ranging from 7% to 11% in the ARS-Ab group and 0% to 48% in other MSA, including Mi2, SRP and TIF-1γ. Fiorentino et al.[27] assessed patients with DM and found that the presence of either NXP-2 or TIF-1γ identified 83% of the patients with cancer, and the presence of one of these antibodies was associated with an increased risk of malignancy. We performed malignancy screening CT on the chest, abdomen and pelvis in all our patients. Similar to Fiorentino et al. study, one patient with TIF-1γ- positivity was found to have a GIST. All of our patients have never presented with acute respiratory failure and had never been diagnosed with ILD before this admission. High-dose corticosteroids were given to all patients, and all of them responded well.

CONCLUSION

IIM ILD can present initially as ARDS. ARDS as an initial presentation is rare and poses diagnostic dilemmas and management challenges. Early diagnosis of ILD in patients admitted with acute respiratory failure is crucial to prevent adverse outcomes. Early diagnosis is crucial to prevent adverse outcomes. Early initiation of corticosteroids and management with optimal ventilator support is essential to improve clinical, radiological and functional status in these patients. The literature on non anti jo1 IIM ILD is sparse and requires further research.

Statement of ethics

The written informed consent to publish the case was taken from the Next of Kin, and the study protocol was approved by the departmental and institute’s committee of medical research.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.