Diagnosis of Digital Ischemia During the COVID-19 Pandemic: A Study From a Developing Country
Bidhan Neupane, Md Nazrul Islam, Abul Khair Ahmedullah, Haner Direskeneli, Md Saif Ullah Khan
TL;DR
This study explores the causes of digital ischemia in Bangladesh during the pandemic, finding that connective tissue diseases and vasculitis are common.
Contribution
The study provides insights into the etiology of digital ischemia in a developing country context during the COVID-19 pandemic.
Findings
Connective tissue disease-associated vasculitis was the most common cause of digital ischemia.
Systemic sclerosis and peripheral arterial disease were significant causes of vasculopathy.
Fever, arthralgia, and high CRP were significantly associated with vasculitis.
Abstract
Objective: Digital ischemia (DI) is an uncommon condition. Information on the etiology of DI is limited. This study aimed to determine the diagnosis of DI in a tertiary care center in Bangladesh. Methods: This cross-sectional study was conducted in the rheumatology department of Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh, from September 1, 2020, to August 31, 2021. A total of 25 consecutive patients with DI were enrolled. Each patient was assessed following the classification/diagnostic criteria for vasculitis and vasculopathy. The 2012 International Chapel Hill Consensus Conference on the Nomenclature of Vasculitides was used for case definition. The study subjects were divided into vasculitis and vasculopathy groups. Fisher’s exact and Student’s t-tests were used to compare the groups. Results: The mean age was 35.88 years with a female predominance…
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| Variable | Number (%) |
| Disease duration in months (mean ± SD), median (IQR) | 24.72 ± 30.78, 12 (2.50-42.00) |
| Constitutional features | |
| Fever | 8 (32) |
| Arthralgia/arthritis | 16 (64) |
| Myalgia | 4 (16) |
| Weight loss | 13 (52) |
| Co-morbidities | |
| Hypertension | 6 (24) |
| Diabetes (including prediabetes) | 9 (36) |
| Dyslipidemia | 22 (88) |
| Coronary artery disease | 2 (8) |
| Variable | Mean ± SD, median (IQR) | Reference range |
| Hemoglobin (g/dL) | 11.54 ± 1.84 | 12-14 (female)/14-16 (male) |
| WBC count (/cumm) | 9834 ± 4749.65 | 4000-11000 |
| Platelet count (/cumm) | 332400 ± 150552.32 | 150000-450000 |
| ESR (mm in 1st hour) | 42.52 ± 34.98, 33 (25.00-44.00) | 10 (male)/20 (female) |
| CRP (mg/L) | 27.39 ± 46.55, 8.2 (3.07-23.07) | <6 |
| Serum creatinine (mg/dL) | 0.74 ± 0.19 | 0.6-1.2 |
| ALT (U/L) | 33.60 ± 32.99, 23 (17.00-41.00) | 10-40 |
| FBS (mmol/L) | 6.27 ± 4.48, 4.8 (4.35-6.25) | 3.9-6.1 |
| BS 2 hours ABF (mmol/L) | 8.80 ± 6.18, 6.6 (5.75-10.10) | 7.8-11 |
| Total cholesterol (mg/dL) | 168.48 ± 55.14 | <200 |
| HDL cholesterol (mg/dL) | 36.84 ± 13.36 | >40 |
| LDL cholesterol (mg/dL) | 90.36 ± 31.00 | <130 |
| Triglyceride (mg/dL) | 206.24 ± 196.26, 164 (116.00-223.00) | <150 |
| Nomenclature | n (%) | Diagnosis |
| Vasculitis (n=15) (based on 2012 International Chapel Hill Consensus Conference) | ||
| Large-vessel vasculitis | 1 (4) | Takayasu arteritis+ |
| Medium-vessel vasculitis | 0 (0) | |
| Small-vessel vasculitis | 0 (0) | |
| Variable vessel vasculitis | 0 (0) | |
| Single-organ vasculitis | 0 (0) | |
| Vasculitis associated with systemic disease (n=14) | 11 (44) | Lupus vasculitis∆+ |
| 2 (8) | Rheumatoid vasculitis+ | |
| 1 (4) | Dermatomyositis vasculitis+ | |
| Vasculitis associated with probable etiology | 0 (0) | |
| Vasculopathy (n=10) | ||
| Systemic sclerosisǂ | 5 (20) | |
| Peripheral arterial disease | 4 (16) | |
| Primary antiphospholipid syndrome | 1 (4) |
| Variable | Vasculitis (n=15) | Vasculopathy (n=10) | P-value |
| Age in years (mean ± SD) | 35.27 ± 11.74 | 36.80 ± 12.29 | 0.76s |
| Gender | 0.60f | ||
| Female | 11 | 7 | |
| Male | 4 | 3 | |
| Smokers | 3 | 3 | 0.46f |
| OCP users | 4 | 2 | 0.56f |
| BMI (mean ± SD) | 21.08 ± 3.43 | 22.54 ± 5.26 | 0.41s |
| Underweight | 4 | 1 | |
| Normal | 7 | 6 | |
| Obese and overweight | 4 | 3 | |
| Disease duration in months (mean ± SD) | 28.20 ± 36.85 | 19.50 ± 19.05 | 0.45s |
| Constitutional features | 15 | 6 | 0.02f* |
| Fever | 8 | 0 | 0.01f* |
| Arthralgia or arthritis | 13 | 3 | 0.01f* |
| Myalgia | 3 | 1 | 0.47f |
| Weight loss | 9 | 4 | 0.28f |
| Co-morbidities | 14 | 8 | 0.35f |
| Hypertension | 3 | 3 | 0.46f |
| Diabetes (including prediabetes) | 4 | 5 | 0.22f |
| Dyslipidemia | 14 | 8 | 0.35f |
| Coronary artery disease | 1 | 1 | 0.65f |
| Variable (unit) | Vasculitis (n=15), mean ± SD | Vasculopathy (n=10), mean ± SD | P-values |
| Hemoglobin (g/dL) | 11.05 ± 1.76 | 12.27 ± 1.80 | 0.11 |
| WBC count (/cumm) | 9534.67 ± 5809.24 | 10283.00 ± 2699.75 | 0.71 |
| Platelet count (/cumm) | 300533 ± 108276 | 370200 ± 189036 | 0.25 |
| ESR (mm in 1st hour) | 44.80 ± 36.52 | 39.10 ± 34.17 | 0.70 |
| CRP (mg/L) | 40.26 ± 36.52 | 8.09 ± 5.97 | 0.04* |
| Serum creatinine (mg/dL) | 0.77 ± 0.22 | 0.71 ± 0.15 | 0.48 |
| ALT (U/L) | 38.20 ± 40.95 | 26.70 ± 14.34 | 0.41 |
| FBS (mmol/L) | 6.60 ± 5.73 | 5.47 ± 1.09 | 0.55 |
| BS 2 hours ABF (mmol/L) | 8.88 ± 7.48 | 8.27 ± 3.53 | 0.81 |
| Total cholesterol (mg/dL) | 173.27 ± 66.76 | 161.30 ± 32.85 | 0.61 |
| HDL cholesterol (mg/dL) | 36.93 ± 15.05 | 36.70 ± 11.11 | 0.97 |
| LDL cholesterol (mg/dL) | 89.33 ± 35.18 | 91.90 ± 25.17 | 0.84 |
| Triglyceride (mg/dL) | 236.40 ± 247.64 | 161.00 ± 59.40 | 0.36 |
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Taxonomy
TopicsSystemic Sclerosis and Related Diseases · Pain Management and Treatment · Long-Term Effects of COVID-19
Introduction
Digital ischemia (DI) is defined clinically as painful digit/s with signs of ischemia or necrosis. The estimated incidence is 2/100,000. It has various etiologies, of which many are poorly understood [1]. The most reported causes are cardiac or arterial embolism, local thrombosis, autoimmune connective tissue diseases (CTDs) such as systemic sclerosis (SSc), vasculitis, or trauma [2].
Among the rheumatic diseases as a cause of limb ischemia, the highest prevalence was observed in patients with SSc and mixed connective tissue disease (MCTD), which approached 90% or greater [3]. The prevalence of Raynaud’s phenomenon (RP) in primary Sjögren’s syndrome (pSS) and systemic lupus erythematosus (SLE) ranged between 13-66% and 10-45%, respectively [4,5]. Up to 17% of patients with rheumatoid arthritis (RA) suffer from this condition [3]. In antiphospholipid syndrome (APS), DI was reported in 3.3-7.5% of cases [6]. Also, 20% of patients with dermatomyositis/polymyositis (DM/PM) and about 50% with undifferentiated connective tissue disease (UCTD) showed this manifestation [7,5]. DI of the upper extremity due to vasculitis was 3.1% and included giant cell arteritis (GCA), Takayasu arteritis (TAK), cryoglobulinemia, necrotizing small vessel vasculitis, and unclassifiable vasculitis. Other studies showed a prevalence of 0-12% [2].
Atherosclerotic peripheral arterial disease (PAD) was seen in 4.3-29% of adults and mainly involved the lower limbs [8,9]. It is an emerging issue in low- and middle-income countries due to increasing traditional cardiovascular risk factors [10]. Digital gangrene was present in more than 70% of patients with thromboangiitis obliterans (TAO) [11], but different studies showed variable distribution ranging from 0% to 22% [2]. DI associated with cancer (DIAC) was 12-15% [12], whereas other studies found up to 8% [2]. The prevalence was 0-33% for hypothenar hammer syndrome (HHS), 0-9.3% for drugs, 2.8% for trauma, 2.5% for thoracic outlet syndrome, 2.2% each for thrombophilia and infectious disease, 1.5% for vasospasm, and 0.9% for peripheral embolism [2].
So far, there are few studies on the etiology of DI and its prevalence. To our knowledge, information on DI from the Asia-Pacific region is limited and unavailable. To date, no study has been published from Bangladesh. Therefore, this study aimed to determine the diagnosis of DI at a tertiary rheumatology center in Bangladesh.
Materials and methods
This observational cross-sectional study was conducted in the department of rheumatology of Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh, from September 1, 2020, to August 31, 2021. Both male and female patients ≥18 years of age with DI (RP and/or digital ulcer/necrosis), giving consent to participate in the study, were included. Patients ≥18 years and not giving consent or below 18 years of age were kept in the exclusion criteria. A total of 25 consecutive patients were enrolled after having informed written consent.
RP was defined clinically as a well-demarcated color change of digit(s). Each patient was evaluated with a thorough history and clinical examination. For body mass index (BMI), Asia-Pacific classification was followed. Investigations like reverse transcription-polymerase chain reaction (RT-PCR) for COVID-19, complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum creatinine, alanine transaminase (ALT), blood sugar (fasting and two hours after breakfast), fasting lipid profile, urine routine and microscopic examination (RME), chest X-ray posteroanterior (PA) view, 12 lead electrocardiogram (ECG), and duplex ultrasonography study of involved limb(s), were sent in every patient. Other tests like glycated hemoglobin (HbA1c), anti-centromere antibody (anti-centromere Ab), anti-topoisomerase I antibody (anti-Scl 70 Ab), nail-fold capillaroscopy, echocardiography, high-resolution computed tomography (HRCT) of chest, anti-ribonucleoprotein antibody (anti-RNP Ab), antinuclear antibody (ANA), anti-double-stranded DNA antibody (anti-ds DNA Ab), anti-Smith antibody (anti-Smith Ab), complement component 3 (C3), complement component 4 (C4), lupus anticoagulant, anti-cardiolipin antibody (anti-cardiolipin Ab), anti-beta-2 glycoprotein 1 antibody (anti-β2 GP1 Ab), anti-Ro/Sjögren’s-syndrome-related antigen A antibody (anti-Ro/SSA Ab), anti-La/Sjögren’s-syndrome-related antigen B antibody (anti-La/SSB Ab), lip biopsy, rheumatoid factor (RF), anti-cyclic citrullinated peptide antibody (ACPA), creatine kinase (CK), aldolase, aspartate transaminase (AST), lactate dehydrogenase (LDH), electromyography (EMG), muscle biopsy, perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA), cytoplasmic anti-neutrophil cytoplasmic antibody (c-ANCA), angiography, hepatitis B surface antigen (HBsAg), anti-hepatitis C virus antibody (anti-HCV), and blood culture and sensitivity (C/S) were requested when indicated. All investigations were performed in BSMMU.
Data were collected and recorded in a semi-structured datasheet (Appendix A). A flowchart was made for each patient with all the related information about the onset and course of illness. For diagnosis, established classification/diagnostic criteria for vasculitis and vasculopathy were used. Study subjects were divided into vasculitis and vasculopathy groups. The case was defined using the 2012 International Chapel Hill Consensus Conference on the Nomenclature of Vasculitides. DM, RA, and SLE were described as CTDs. In cases of overlap, the etiology was derived from the disease activity status (e.g., in the case of SLE and RA overlap, diagnosis of lupus vasculitis was made based on active SLE). Bias was tried to overcome by following the above-mentioned process. Data were entered in IBM SPSS Statistics for Windows, Version 26 (Released 2020; IBM Corp., Armonk, New York, United States), and the level of significance was analyzed between two groups using Fisher’s exact test for gender, smoking, oral contraceptive pill (OCP) use, constitutional features, and co-morbidities. Student’s t-test was used for age, BMI, disease duration, hemoglobin, WBC count, platelet count, ESR, CRP, serum creatinine, ALT, blood sugar (fasting and two hours after breakfast), total cholesterol, HDL cholesterol, LDL cholesterol, and triglyceride. The confidence interval (CI) was set at 95%. P-value <0.05 was considered significant.
Results
There were 18 women (72%) and seven men (28%) with a female-to-male ratio of 2.6:1. The mean age was 35.88 ± 11.73 years (range, 20-60 years). Among the occupations, 16 cases (64%) were homemakers, seven (28%) others, and two (8%) unemployed. A single subject (4%) was illiterate. Only male patients were smokers. Among six smokers, two cases with PAD were current smokers, and the other four (one SLE, one RA, one DM, and one PAD) were ex-smokers. None had a history of substance abuse. Six women (four SLE, one PAS, and one SSc) used OCPs. The mean BMI was 21.67 ± 4.22 kg/m^2^; five (20%) were underweight, 13 (52%) normal, and seven (28%) were overweight and obese together.
None of the study subjects had a family history of sudden death, an autoimmune disease in first-degree relatives, recent trauma, or a positive COVID-19 test. The clinical and laboratory characteristics of study subjects are shown in Tables 1-2, respectively.
The diagnoses of DI are shown in Table 3. Among all the cases, 84% had rheumatic conditions. The most common etiology was CTD (56%).
The clinicodemographic and laboratory characteristics of the vasculitis and vasculopathy groups are shown in Tables 4-5, respectively.
In our study, four cases (16%) were PAD (three men and one woman). Two male patients were less than 40 years of age. Two subjects, one male and one female, had upper limb involvement. In the male subgroup, the risk factors of PAD were smoking, obesity, hypertension, diabetes, and dyslipidemia in three, one, one, two, and three cases, respectively. The female patient with PAD had obesity, hypertension, and dyslipidemia.
Discussion
DI may progress to a critical stage. A careful consideration of various etiologies during assessment is imperative. Early and correct diagnosis of DI is often challenging for clinicians. Due to overlapping features of several diseases, using classification/diagnostic criteria may help in quick assessment in resource-constrained settings.
In our study, most subjects (56%) had CTD. Raimbeau et al. found CTD as the most common cause (19%) of DI, including SSc (3.1%). Other studies have shown CTD as an etiology of limb ischemia in up to 49% of cases. The prevalence of CTD, except SSc, in those studies varied from 0% to 28%. Among nine published articles on DI, seven had shown CTD as the most common etiology [2]. The high prevalence of CTD in the present study may be due to our rheumatology referral center status, and the wide variation may be due to enrollment criteria.
The mean age of subjects with DI was 35.88 years (range, 20-60 years), with a female predominance (72%). Also, all cases of CTD were between 20 and 60 years of age. These observations were similar to those of Gaubitz [13] and Spagnolo et al. [14]. They have mentioned that CTD was common among women between 15 and 60 years of age.
Compared to the general population, traditional risk factors for atherosclerosis are higher in patients with CTD [15]. In our study, the rate of hypertension (24%) and diabetes (including prediabetes) (36%) was high, but among the CTD cases, 8% had hypertension and 16% had diabetes (including 4% prediabetes). A similar finding for diabetes (12%) but not for hypertension (28%) was reported from China [16]. The cause was unknown for the low prevalence of hypertension in the present study. In this study, 88% of total cases and 52% of subjects with CTD had dyslipidemia. Avinash et al. showed dyslipidemia in 80% of patients with CTD (including 27% SSc cases), comparable to our result [17]. Early identification of those risk factors in CTD patients and subsequent steps may reduce the complications.
In our study, out of 15 cases of vasculitis, a single case was TAK, and the others were vasculitis associated with CTDs. Among them, 11 (44%) were lupus vasculitis (nine classic SLE, one SLE/RA overlap, one SLE/TAK overlap), two (8%) rheumatoid vasculitis, and one (4%) DM vasculitis. Vasculitis occurred in around half of the patients with SLE [18], and lupus vasculitis was “probably the most common cause of vasculitis-associated digital ischemia” [11].
Among the vasculopathies, SSc (20%) was the most common cause of DI. A similar observation was noted by Raimbeau et al. [2]. All had RP as a presenting feature, a similar finding to that reported by Walker et al. [19].
The rate of PAD (16%) in this study was within the range mentioned by Weinberg and Jaff [8]. Fifty percent of our PAD cases were under 40 years of age and had DI in the upper limbs with several traditional risk factors. Similar findings were shown by Upganlawar et al., who disclosed that such an occurrence is possible in the presence of conventional risk factors of atherosclerosis [20].
In the present study, fever, arthralgia/arthritis, and high CRP favored vasculitis. CRP, one of the markers of inflammation, is used to rule out vasculitis [21] and is markedly elevated with active disease [22]. Constitutional symptoms and acute phase response may suggest vasculitis [11]. During a case evaluation, the presence of these markers may guide the diagnosis of vasculitis.
In this study, none had occupations requiring vibrating tools, though Cordeiro and Andrade mentioned such tools as one of the risk factors for DI [23]. We observed no correlation between education level and DI, similar to a study from Greece [24].
Strength of the study
This study to determine the diagnosis of DI using established classification/diagnostic criteria is the first in Bangladesh. Our study can help to develop a proposal for early diagnosis and initiation of treatment in resource-constrained settings and to calculate the sample size for vasculitis.
Limitations of the study
There are several limitations of this study. As an observational study done in the rheumatology department of a tertiary care hospital, our study may not cover all the cases of vasculitis- and vasculopathy-associated DI in the community. This was a thesis work done during the COVID-19 period, so the total sample could not be enrolled. Duplex study (in four patients) and biopsy could not be done for COVID-19 reasons. All the tests for APS were not possible for patients due to resource constraints. Repeat tests, when required, were not performed because of the study design.
Conclusions
In a tertiary rheumatology center, vasculitis associated with CTDs is more common in patients with DI. Lupus vasculitis and SSc were the most common causes of DI among the vasculitis and vasculopathy cases, respectively. Patients with PAD can present before the age of 40 years and with ischemia in the upper limb.
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