Impact of COVID-19 pandemic on healthcare delivery for lysosomal storage disorders at a tertiary care public hospital in Mumbai

ABSTRACT

Introduction:

Management of lysosomal storage disorders (LSDs) requires periodic visits for medical surveillance and hospitalizations. Management of LSDs may have been adversely impacted during the COVID-19 pandemic.

Objective:

To identify the factors impacting health care for patients with LSDs during the COVID-19 pandemic.

Methods:

An observational study was conducted in Mumbai comparing infusion practices and reasons for missed infusions for 15 months before March 2020 versus two phases during the pandemic (April 2020–March 2021 and April 2021–March 2022) in patients receiving intravenous enzyme replacement therapy (ERT) and on oral substrate reduction therapy (SRT).

Results:

Fifteen patients with LSDs were enrolled. Before the pandemic, 6/13 (46%) were receiving ERT at the study site, 4/13 (31%) at a local hospital, and 3/13 (23%) at home; two were on SRT. The median distance traveled for receiving ERT was 37 km, and 4.4 infusions/patient were missed. From April 2020 to March 2021, two more patients opted for home ERT infusions. The median distance traveled for receiving ERT was 37 km, and 11.6 infusions/patient were missed. From April 2021 to March 2022, one more patient opted for home ERT infusions. The median distance traveled for receiving ERT was 7 km, and 5.6 infusions/patient were missed. The pandemic also affected SRT compliance adversely. For all patients, the cause of disrupted treatment was travel curbs (69%) and fear of getting COVID-19 infection (38%).

Conclusions:

Treatment of LSDs was disrupted during the pandemic, with an increase in missed ERT infusions and SRT doses.

Introduction

The coronavirus disease 2019 (COVID-19) was declared a pandemic by the WHO on March 11, 2020.[1] The Government of India (GoI) declared a nationwide lockdown from midnight of March 24, 2020,[2] which disrupted routine healthcare and supply chains of medicines. Shut down of transport and curfews prevented patients from reaching healthcare facilities.[2] The study site is a center for managing patients with lysosomal storage disorders (LSDs). During the pandemic, the study site served as a critical covid care center. Stringent lockdown continued in Mumbai up to May 31, 2020, and continued till January 2021, when phased relaxation commenced.[3,4] Subsequently, the second wave of the pandemic began in February 2021, which compounded the situation.[3]

Raman et al.[5] documented the adverse impact of the pandemic on routine health care during the stringent lockdown period and in severely affected areas in India.[5] As Mumbai was the second most afflicted city in the state of Maharashtra,[3] we hypothesized that healthcare delivery for LSDs would have been adversely affected at our study site during the pandemic. The aim of the present study was to assess the impact of the pandemic on the management of LSD patients at our center.

Methods

A single-center, observational, retrospective data analysis was conducted telephonically after approval from the institutional ethics committee (IEC/OUT/164/2022, dated March 10, 2022). The present study was conducted as per ICMR guidelines issued during the COVID-19 pandemic.[6] Patients who had been receiving therapy for at least 6 months before the commencement of the lockdown were enrolled in the present study after obtaining signed informed consent from parents or patients by WhatsApp.[6]

Prior to the pandemic, patients were visiting the center on a daycare basis for enzyme replacement therapy (ERT) infusions for mucopolysaccharidosis (MPS) weekly or for Gaucher disease (GD) two-weekly. Sanofi Healthcare India Pvt. Ltd. (through parent company Sanofi Specialty Care, USA) and Takeda Biopharmaceuticals India Pvt. Ltd. were providing the ERT and substrate reduction therapy (SRT) through their respective charitable access programs. These prohibitively expensive medications were being imported and then transported to our center. All patients receiving oral SRT and ERT (at local infusion centers near their place of residence or at home) were visiting the center to collect their medications every 3–6 months.

When the pandemic began, a WhatsApp text was sent to all LSD adult patients and parents of children about personal protection practices and COVID-related precautions/symptoms as recommended by Mistry et al.[7] during the pandemic, with instructions to contact the center for any health- or medication-related issues. Patients were also offered the option for delivery of ERT vials to their residence. However, those receiving SRT had to visit our department to collect medication as per manufacturer’s directive. Subsequently, when COVID vaccine was made available by the GoI, patients eligible for vaccination were similarly advised to get vaccinated.

Participants’ demographic data and treatment-related information were recorded. The dates of infusion, number of missed infusions (defined as infusion not administered within 3 days of scheduled date) and missed monitoring visits, place of infusion, distance of infusion site from home, mode of transport to the infusion site, and the reason for missed infusions were obtained during (i) the 15-month period preceding the pandemic (January 2019–March 2020); (ii) the first year of the pandemic (April 2020–March 2021, coinciding with stringent lockdown, 1^st wave from March 2020 to February 2021, and the onset of 2^nd wave in March 2021); and during the second year of the pandemic (April 2021–March 2022, coinciding with the availability of COVID-19 vaccine and phased unlocking). Data about COVID-19 infection and COVID-19 vaccination in patients were recorded.

Patients opting to take infusions at the study site during the pandemic underwent RT-PCR testing for SARS CoV-2 infection, and those testing negative were administered ERT infusion.

Data were descriptively analyzed using median and range for continuous variables and frequency and proportion for categorical variables. Analysis was performed using IBM SPSS Statistics for Windows, version 25.0 (IBM Corp., Armonk, N.Y.).

Results

Seventeen patients receiving ERT or SRT at our center before the pandemic were screened, and 15 (including 5 adults) were enrolled (11 males and 4 females; M: F ratio = 2.7:1). These included 14 patients with GD. Of these, 10 (67%) (3 adults) were receiving ERT namely imiglucerase, and two (13%) children were receiving velaglucerase. Another two (13%) adult patients with GD were on SRT with eliglustat tartrate and were previously receiving imiglucerase up to 19 years of age. One child (7%) with Hunter syndrome was receiving ERT, namely idursulfase alfa.

Of the 15 patients, four were residents of Mumbai, 10 were from other parts of Maharashtra, and one resided in the neighboring state of Gujarat. The median distance from their place of residence to our center was 54 km (range: 1.2–928 km). The median age at enrolment was 15.2 years (range: 4.8–33.2 years). The median age at initiation of ERT was 3.3 years (range: 1.9–15.5 years) and 19 years for initiation of SRT. The median duration of treatment before March 2020 was 10.3 years (range: 0.6–20 years).

Infusion practices of 13 patients receiving ERT before and during the pandemic are presented in Table 1 and Figure 1. After March 2020, 2/13 (13%) patients started receiving their ERT vials at their residence. Before the pandemic, 9/13 (69%) patients missed a total of 40 infusions (4.4 infusions/patient). During April 2020–March 2021, 9/13 (69%) patients missed a total of 105 infusions (11.6 infusions/patient). Of these nine patients, two received no medication for 1 year as both had relocated to their village. Gaucher disease status of both the patients who missed ERT infusion for 1 year was stable [Supplementary Table 1], except for a 2.5 times rise in plasma chitotriosidase in patient 2 and reduction in platelet count by 50% in patient 3 during the pandemic period in comparison to pre-pandemic levels. Between April 2021 and March 2022, 10/13 (77%) patients missed a total of 56 infusions (5.6 infusions/patient).

Table 1.

Comparison of infusion practices for enzyme replacement therapy before and during the COVID-19 pandemic (N=13)

	January 2019–March 2020 (Pre-COVID-19)	During the pandemic, from March 2020 onwards
		April 2020–March 2021	April 2021–March 2022
1. Infusion site (N=13)
At study site	6 (46%)	4 (31%)*	2 (16%)#
Local healthcare facility	4 (31%)	4 (31%)	5 (38%)
Home	3 (23%)	5 (38%)	6 (46%)
2. Mode of transport to the infusion site	N=10	N=8	N=7
Outstation travel
Bus	2 (20%)	2 (25%)	1 (14.3%)
Train	3 (30%)	2 (25%)	1 (14.3%)
Local, own vehicle	5 (50%)	4 (50%)	4 (57.1%)
Walking to infusion site (local hospital near residence)	-	-	1 (14.3%)
3. Distance (km) from residence to infusion site	N=10	N=8	N=7
Median (range)	37 (0.8–470)	37 (5–260)	7 (0.8–260)
4. Visits to study site for infusions
Gaucher disease, twice weekly infusion (N=12)
Total no. scheduled	29	27	26
No. of missed infusions- median (range)	3 (0–9)	6 (0–26)	2 (0–16)
Hunter syndrome on weekly infusions (N=1)
Total no. scheduled	52	53	52
Total no. administered	52	53	51
Total no. missed over 1 year	0	0	1
No. of patients with missed infusions
No missed infusions	4 (30.8)	4 (30.8)	4 (30.8)
1 missed infusion	-	-	3 (23)
2 missed infusions	2 (15.4)	1 (7.7)	1 (7.7)
≥3 missed infusions	7 (53.8)	8 (61.5)	5 (38.5)

*Two patients had relocated to their village and did not receive a single ERT infusion, # of the two patients, one received 8/24 infusions, and the other received 17/26 infusions

Figure 1.

Comparison of infusion practices before the pandemic and in the two phases of the pandemic (April 2020–March 2021 and April 2021–March 2022) showing: (a) changes in the site of infusion, with an increasing proportion opting for home infusions over the course of the pandemic; (b) changes in the mode of transport for visiting infusion site; and, (c) the number of patients missing infusions was maximum during April 2020–March 2021, with a decrease in the number of patients missing infusions and number of infusions during April 2021–March 2022

Supplementary Table 1.

Clinical, hematological, and biochemical parameters before and after the COVID-19 pandemic of two patients who had missed ERT infusions for 1 year

Parameter	Normal range	Patient 2			Patient 3
		2018	2021	2023	2018	2021	2023
Duration of ERT (years)	-	1	4	6	6	9	11
Weight (kg)	-	14	20	24	17	23	30.4
Height (cm)	-	92	111	123	112	132	140
Liver size (cm below costal margin)	-	10	5	1	1	Not palpable	Not palpable
Liver volume (cc) by ultrasonography	-	1293	732	539#	-	1080	1011#
Spleen size (cm below costal margin)	-	20	4	2	13	11.5	2
Spleen volume (cc) by ultrasonography	-	1695	190	495#	-	510	1178#
Plasma chitotriosidase*	8–87 nmol/h/mL	4255	2286	1113	-	-	-
Hemoglobin (g/dL)	-	11.1	11.3	12.4	10.8	10.9	11.6
White cell count/cmm	-	7900	8100	6800	6800	4500	5100
Platelet count/cmm	-	220,000	210,000	300,000	180,000	90000	110000
AST/ALT	<40 IU/L	29/23	46/18	45/30	36/20	40/60	39/25
Serum calcium	9–11 mg/dL	8.9	8.6	9.1	8.4	9.7	7.3
Serum phosphorus	2.5–7 mg/dL	4.6	4.3	3.4	5.3	4.6	4
Serum alkaline phosphatase	50–370 U/L	213	379	188	-	136	192
Serum iron	15–128 µg/dL	50	-	-	67	56	56
Total iron binding capacity	185–415 µg/dL	237	-	-	293	392	329
Transferrin saturation	14%–50%	21	-	-	23	15	16
Serum ferritin	7–140 ng/mL	155	-	-	502	-	385
RBC folate	523–1257 ng/mL	401	-	-	-	3.5	-
Serum Vitamin B12	197–771 pg/mL	456	196	-	-	600	54
Serum 25 hydroxy Vitamin D	Deficiency <20 ng/mL	17.3	34	-	11.7	9.71	13.7
DEXA Z-score	-			-
Spine		−0.6	−1.1		−0.5	- 0.6	- 0.3
Total femur R/L		- 0.6/ - 0.1	- 0.0		- 0.2/ - 0.2	- 0.7/ - 0.6	- 0.6/ - 0.2
MRI abdomen	-	Moderate hepatomegaly Massive splenomegaly Splenic infarcts	Moderate hepato- splenomegaly No new splenic infarcts	Hepatosplenomegaly without abnormal signal intensity	Mild hepatomegaly, small infarct in segment VI of right liver lobe, moderate splenomegaly	-	Enlarged liver with normal contour, margins and signal intensity. Enlarged spleen with normal signal intensity
MRI of both femurs	-	-	-	Normal signal intensity	-	-	Heterogenous marrow signal intensity in both femur shafts with focal hypointensity
Cardiac 2D echocardiography		Normal	Normal	-	Normal	-	-

*Plasma chitotriosidase activity of Patient 3 was normal at baseline most likely due to the presence of a null allele of the CHIT1 gene; hence, the biomarker was not useful for tracking response to enzyme replacement therapy. #Organ volume assessment by MRI abdomen

Reasons for disrupted ERT infusions are presented in Table 2 and Figure 2. Eight patients stated more than one reason for missing their infusions. Reasons for missed home ERT infusions in four patients of GD were travel curbs and fear of infection (2 patients each) and professional commitment (duty), temporary relocation to village, import delay, monetary difficulty and influenza-like illness (1 patient each). The child with Hunter syndrome missed one infusion in April 2021 (during the second wave of the pandemic) due to COVID-19 infection. Information about the reasons for missing monitoring visits to our center is presented in Table 3.

Table 2.

Reasons for missing ERT infusions: Comparison before and during the COVID-19 pandemic (N=13)

Reasons for missed infusions	Before March 2020 (January 2019–March 2020)	After March 2020
Unable to travel to the infusion site	-	9 (69%)
Temporary relocation to native place	-	4 (31%)
Infusion site closed or converted to COVID-19 center
Fear of going to hospital/getting	NA	-
COVID-19 infection	NA	5 (38%)
Delays in the import of medicine	-	2 (15.4%)
Delays in the transport of medicine to infusion site/residence	4 (31%)	1 (7.7%)
COVID-19 infection in patient	NA	2 (15.4%)
COVID-19 infection in family member	NA	-
Monetary constraints	3 (23%)	3 (23%)
Other cause(s):	4 (31%)	2 (15.4%)
Social obligation	2 (15.4%)	-
Family member unwell	1 (7.7%)	-
Professional commitment (duty)	1 (7.7%)	1 (7.7%)
Marital discord (parents separated)	-	1 (7.7%)

Figure 2.

Comparison of reasons for missed infusions before the pandemic (a) and during the pandemic (b)

Table 3.

Comparison of reasons for missing monitoring visits for patients on ERT before and during the COVID-19 pandemic

	Before March 2020 (January 2019–March 2020)	After March 2020
Monitoring visits (N=13)
Total no. scheduled/patient/year	1	1
Total visits missed/scheduled visits	7/13 in 1 year (53%)	17/26 in 2 years (88%)
Reasons for missed monitoring visit (N=13)
Unable to travel to the infusion site	-	4 (31%)
Temporary relocation to native place	-	2 (15.4%)
Infusion site closed or converted to COVID-19 center	NA	-
Fear of going to hospital/getting COVID-19 infection	NA	10 (77%)
COVID-19 infection in patient	NA	-
COVID-19 infection in family member	NA	-
Monetary constraints	5 (38.4%)	3 (23%)
Other cause(s)	2 (15.4%)	-
Personal commitments	1 (7.7%)	-
Job-related commitment	1 (7.7%)	-

Two patients who were receiving SRT eliglustat were traveling 14.5 and 29.5 km, respectively, to our center from their residence by car and train, respectively, for stockpiling their medication. Neither of them had missed any dose or monitoring visit before the pandemic. However, after the pandemic, one missed 14 out of 730 (2%) doses, and the other missed 15 out of 365 (4%) doses during April 2020–March 2021. Similarly, during April 2021–March 2022, they missed 7/730 (1%) and 15/365 (4%) doses, respectively. Doses of eliglustat were missed by both patients due to delay in importing medication and in one due to fear of getting COVID-19 infection while visiting our center to collect the drug. Both these patients missed monitoring visits due to fear of getting COVID-19 infection.

Two adults with GD who had influenza-like illness for 1 week in January 2022 recovered with symptomatic treatment but had not undergone testing for SARS-CoV-2 infection. RT-PCR testing performed as part of contact tracing detected SARS-CoV-2 infection in the child with Hunter syndrome who remained asymptomatic.

The number of patients visiting our center for ERT infusions decreased from 6/14 (46%) before the pandemic to 4/13 (31%) during April 2020–March 2021 and two patients during April 2021–March 2022 [Table 1]. These two patients receiving ERT at our center received 25 and nine ERT infusions (April 2020 and March 2021), respectively, and eight and 17 infusions (April 2021–March 2022), respectively, and did not test positive during their visits. With the increasing adoption of home or local infusion practices, median distance traveled for receiving ERT decreased from 37 km before and during the pandemic period of April 2020–March 2021 to 7 km during April 2021–March 2022.

Of the four patients with GD, one family member was diagnosed to have COVID-19 infection. A paternal uncle of a patient with GD succumbed to COVID-19 infection in April 2021. Nine of 15 participants (60%) were eligible for COVID-19 vaccination, of which seven (47%) got vaccinated (6 received two doses).

Discussion

The present study documents a change in ERT infusion practices for patients with LSDs being managed at our center in Mumbai city during the COVID-19 pandemic. During the first phase of the pandemic (April 2020–March 2021), there was a threefold rise in disruption of ERT infusions in patients with LSDs, although the median distance traveled for infusions remained the same. However, during the second phase of the pandemic (April 2021–March 2022), the number of missed ERT infusions in these patients almost returned to the pre-pandemic level (5.6/patient/year vs. 4.4/patient/year). The reason for this was a nearly twofold rise in the number of patients opting for taking infusions at home or a local hospital (7 vs. 3); which was reflected in the median distance traveled to take infusions reducing by almost 80% (7 km vs. 37 km). There was only a minimal (1%–4%) disruption in oral SRT doses during both phases of the pandemic. Although there were some delays in importing medications and their transportation to our center, these two factors resulted in missed doses in only a minority of patients (15% and 8%, respectively). In the present study, the patients’ monetary constraints did not result in missed infusions as they opted for taking ERT either at home or at a local hospital. However, the pandemic adversely affected the patients’ annual monitoring visits (88% vs. 53%) to our center, either due to fear of getting COVID-19 infection and/or rigorous travel restrictions.

The most frequently cited reasons for missing ERT infusions in the present study were rigorous travel curbs in 69% and fear of visiting a hospital or getting SARS-CoV-2 infection in 38% who missed infusions and 77% who missed monitoring visits. Kahraman et al.[1] (Ankara, Turkey) reported their experience in managing 75 patients with LSDs (2–58 years old) over 4 months (July 2020–October 2020). In their study, 35/75 (46%) patients missed infusions despite the absence of stringent lockdown even though 67/75 (89%) patients were receiving infusions near the place of residence with traveling distances of 1–50 km. Comparatively, 9/13 (69%) patients missed infusions in the present study and traveled longer distances of 5–260 km during April 2020–March 2021. Sechia et al.[8] reported their experience in managing 102 patients (mean age: 38.8 ± 18.6 years) from 16 regions in Italy during the pandemic; 27/55 (49%) patients receiving infusions in the hospital missed ERT infusions despite uninterrupted drug supply and delivery being ensured.[8] Reasons for missed infusions in Italy were fear of infection (63%), reorganization of infusion center (37%), and feeling unwell (15%).[8]

Fear was the most frequently cited reason for missing hospital-based ERT infusions in 26/35 (74%) patients in Turkey receiving ERT or SRT and in 17/27 (63%) patients in Italy.[1,8] Pal et al. (New Delhi)[9] also documented anxiety and fear of the pandemic in 12/26 (46%) with LSDs or their parents, with heightened worry during hospital visits for ERT in 8/12 (66%). However, fear of getting COVID-19 infection as a reason for interrupting ERT infusion was reported by only 1/20 (5%) patients who missed infusions. The most frequently cited reasons in 20/26 (77%) patients who missed ERT in the study by Pal et al.[9] were inability to collect ERT vials due to transport restriction in 13/20 (65%), closure of local infusion hospital in 4/20 (20%), and delayed import in 2/20 (10%).

In the absence of data in the early phase of the pandemic, patients with LSDs were speculated to be at high risk of developing life-threatening complications or high mortality due to multiorgan disease involving the heart, kidney, and respiratory system.[1] GD was considered a high-risk population due to the similarity in pathophysiology of lysosomal disruption and immune-inflammation with SARS-CoV-2 infection.[7] Thus, anxiety and worry about the risk of infection and developing complications could be justified in a study by Andrade-Campos et al. (Spain),[10] wherein 50/110 (55%) patients with GD were older than 50 years and 38/110 (34%) had comorbidities, placing them at risk of developing severe COVID-19 infection. In the present study, traveling to our center to take ERT infusions being perceived by patients as putting themselves at risk of developing COVID-19 infection was probably justifiable as Mumbai was one of the worst affected cities in India, with our hospital being a designated referral center for COVID treatment having a high burden of COVID-affected patients. A factor fueling fear or anxiety during the COVID-19 pandemic could have been the continuous deluge of depressing information in media, particularly social media, as reported in a cohort of LSD patients from Italy.[11] Thus, avoiding hospital visits for ERT infusions out of fear of contracting SARS-CoV-2 infection appears to be a common phenomenon in patients with LSDs from diverse geographical regions superseding the necessity of taking ERT infusions during the pandemic.

In the present study, number of infusions missed by those receiving home infusions was 0–12. Reasons for 12 missed home infusions in a person with GD were transport restrictions, fear of contracting COVID-19, and presence of flu-like symptoms. Two home infusions were missed in one patient due to a delay in import, and seven infusions were missed in the other due to relocation to village, travel restrictions, fear of contracting COVID-19, and monetary constraints. A single scheduled home infusion missed by one person in her 20s with GD was due to her being on professional duty. Disruption in treatment for the patient with Hunter syndrome who received home infusions was just one missed infusion due to COVID-19 infection. None of the six patients receiving home infusions in Spain[10] missed infusions, and a single infusion was missed out of 16 receiving home infusions in Italy,[8] compared to 27/55 (49%) experiencing disruption in the hospital setting in Italy and 11/44 (25%) in Spain.[8,10] The practical solution then was to change practices in favor of home infusions. Preference for home infusions in Italy increased from 16/71 (22.5%) by an additional 9/55 (16%) hitherto receiving infusions in hospital switching to home infusions,[8] similar to the result of the present study, wherein the number of patients opting for home infusions almost doubled (an increase from 23% before 2020 to 46% during the 2^nd period of the study from April 2021 to March 2022).

Though there were common themes such as fear of infection precluding hospital visits for ERT infusions and preference for home infusions, it is not possible to compare all other results of the present study with similar studies from other countries such as Turkey, Italy, and Spain and cities within India because the period and magnitude of various COVID-19 waves, stringency of lockdown, organization of health infrastructure, and roll-out of vaccine differed.

In the present study, 1/15 patients of LSD got asymptomatic COVID-19 infection. Reports from Morocco (an asymptomatic 21-year-old with Fabry disease undergoing hemodialysis managed by home-based quarantine), Israel, Australia (one symptomatic 24-year-old pregnant woman with mild disease not requiring treatment among 550 patients having GD), and New York (16 positive out of 88 patients with GD tested for SARS-CoV-2) have documented inconsequential effects of COVID-19 infection in patients with LSDs.[12,13,14,15] Only two splenectomised infected patients with GD out of 110 in the study from Spain succumbed.[10] The present study’s results are similar to other reports that have refuted the speculated heightened risks of COVID-19 mortality in patients with LSDs.

In conclusion, the present study highlights that fear of getting COVID-19 infection while traveling to our center resulted in a sharp decline in annual monitoring visits for patients with LSDs. However, facilitating infusions at home or at a local hospital and disseminating simple but valuable treatment-related information via WhatsApp during the pandemic helped in continuing the treatment of patients with LSDs at our center. It was heartening to note that the patients on oral SRT, although few, continued to travel to our center to collect their medications.

Financial support and sponsorship

Nil.

Conflict of interest

Sunil Karande is the Editor of the Journal of Postgraduate Medicine.