Post-coronavirus disease 2019 (COVID-19) syndrome is defined as signs and symptoms that develop during or after an infection consistent with COVID-19, continue for >12 weeks and are not explained by an alternative diagnosis.1, 2 The UK Government estimates that around one in 10 people testing positive for the causative virus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) will meet this definition,3 although several large surveys of electronic health records suggest that the true incidence may be higher than this.4, 5

The immune system may be dysregulated in patients with haematological diagnoses, whether by the underlying disease, or by its treatment. As an aberrant immune response is implicated in the persistence of symptoms in some patients after COVID-19,6 it is important to investigate how patients with underlying haematological disorders are affected by post-COVID-19 syndrome.

To better understand the nature of the problem we established a clinic aiming to identify and contact all patients under the care of our hospital, with a history of both a haematological diagnosis and previous COVID-19.

PATIENT POPULATION

To identify all patients that had contracted SARS-CoV-2, rather than just those hospitalised with the condition, we combined several search strategies. The unique National Health Service (NHS) numbers of all patients to have been reviewed in any haematology clinic at our hospital in the last 5 years were used to interrogate a database of all SARS-CoV-2 polymerase chain reaction (PCR) tests performed within our region. Patients who had tested positive were identified, and clinic letters reviewed to identify if they had a confirmed underlying haematological diagnosis (as some patients reviewed in clinic were not found to have a primary haematological disorder). Patients with malignant haematological diagnoses were included, whether they had been treated or not for their disorder. We also included patients with a diagnosis of immune thrombocytopenia or cold haemagglutinin disease who were either on treatment or who had had prior immunomodulatory treatment. Patients aged <18 years and those with a diagnosis of monoclonal gammopathy of uncertain significance were excluded. Patients contracting SARS-CoV-2 after 1 May 2021 were excluded.

As some patients with suspected COVID-19 were not formally tested, were tested out of area, or tested negative by PCR despite a clear history and clinical signs, all haematology doctors, specialist nurses, secretaries and chemotherapy schedulers at our hospital were asked to record details of patients who self-reported COVID-19 infection. Infection was then confirmed by reviewing clinical notes from admissions, obtaining positive PCR results for SARS-CoV-2 from other healthcare centres, or by the presence of positive antibodies confirming previous suspected episodes of infection.

Surviving patients were all invited to a post-COVID-19 clinic, a minimum of 12 weeks after their diagnosis, and were all assessed by the same consultant, experienced in the management of patients with haematological disorders, in order to avoid inter-observer variability. Information was gathered on the course of their infection, as well as to determine if they were still suffering with ongoing symptoms. Each consultation lasted 30 min, and followed a predetermined structure of prompts, to ensure that the full range of reported symptoms of post-COVID-19 syndrome were considered.7 The judgement of the physician, as well as the views of the patients were considered in determining whether persisting symptoms could be attributed to previous COVID-19, or rather to the underlying disease or its treatment.

RESULTS

In total, 68 patients with underlying haematological diagnoses and SARS-CoV-2 infection were identified. One patient survived COVID-19 but died from other causes before planned follow-up in clinic, and it was not possible to contact two patients. Of the remaining 65 patients (Table 1), 28 died of their infection, with age being the major risk factor (Figure 1).

TABLE 1. Demographics of patients with haematological disorders contracting severe acute respiratory syndrome coronavirus-2 infection. Comorbidities are listed if present in ≥5% of the total patient population Variable Total Surviving patients Deceased patients Number of patients 65 37 28 Age, years, mean (range) 72 (38–100) 66 (38–90) 80 (67–100) Male, n (%) 43 (66) 22 (60) 21 (75) Diagnosis, n (%) Malignant Lymphoid 36 (55) 19 (51) 17 (61) CLL/SLL 20 12 8 FL 3 3 0 DLBCL 3 2 1 HCL 1 0 1 Hodgkin lymphoma 3 1 2 MALT/LPL/Other low-grade NHL 5 1 4 Mantle cell lymphoma 1 0 1 Myeloid 20 (31) 14 (38) 6 (21) MDS/CMML 6 3 3 AML 2 2 0 MPN 11 8 3 AA with allogeneic stem cell transplant 1 1 0 Myeloma 6 (9) 1 (3) 5 (18) Non-malignant 3 (5) 3 (8) 0 ITP 2 2 0 CHAD 1 1 0 Disease status, n (%) Active disease 31 (48) 16 (43) 15 (54) Previous chemotherapy 44 (68) 25 (68) 19 (68) Previous anti-CD20 treatment 14 (22) 10 (27) 4 (14) Comorbidities, n (%) Hypertension 16 (25) 6 (16) 10 (36) Diabetes mellitus 15 (23) 8 (22) 7 (25) Ischaemic heart disease 14 (22) 9 (24) 5 (18) Congestive cardiac failure 8 (12) 2 (5) 6 (21) Atrial fibrillation 6 (9) 3 (8) 3 (11) Asthma 7 (11) 4 (11) 3 (11) Chronic obstructive airways disease 8 (12) 4 (11) 4 (14) Cerebrovascular disease 6 (9) 3 (8) 3 (11) Chronic kidney disease 5 (8) 2 (5) 3 (11) AA, aplastic anaemia; AML, acute myeloid leukaemia; CHAD, cold haemagglutinin disease; CLL, chronic lymphocytic leukaemia; CMML, chronic myelomonocytic leukaemia; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; HCL, hairy cell leukaemia; ITP, immune thrombocytopenic purpura; LPL, lymphoplasmacytic lymphoma; MALT, mucosal-associated lymphoid tissue lymphoma; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; NHL, non-Hodgkin lymphoma; SLL, small lymphocytic leukaemia.

Outcomes for patients with haematological disorders who had contracted severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Each horizontal bar represents one patient contracting SARS-CoV-2, with the colour denoting whether they survived the episode of infection (survived: blue bar, deceased: red bar). The x-axis shows the age of patients at the time of infection. The mean (SD) age of patients surviving coronavirus disease 2019 (COVID-19) infection was 65·9 (14·7) years, compared with 80·4 (7·6) years for those not surviving (p ≤ 0·001 using Welch t-test)

In all, 37 haematology patients survived infection with SARS-CoV-2, with 20 being admitted to hospital for treatment. The mean length of stay for those admitted was 15·2 days (median of 9 days). None of the surviving patients required admission to the intensive treatment unit, although five patients were treated with continuous positive airway pressure support on a medical escalation unit.

In all, 19 of the 37 patients (51%) reported persistent symptoms meeting the criteria for post-COVID-19 syndrome (Table 2). There was no correlation between the age of the patients and the likelihood of ongoing symptoms (Figure 2). Ongoing shortness of breath (38%) and fatigue (38%) since infection were the most commonly reported symptoms. Worsening mental health, experienced as depression or anxiety since infection (16%) were also relatively common as was cough (14%). Anosmia persisted in 8% of patients, but always in conjunction with additional, and potentially more significant ongoing symptoms. Additional reported symptoms included two patients with rash (5%), one patient with persistent myalgia (3%), and another with hair loss (3%). No patients reported ongoing fevers, abdominal pains, or diarrhoea. Fatigue, shortness of breath, and mood disturbance were all significantly more common in patients who were admitted, rather than those who had not required admission.

TABLE 2. Presence of ongoing symptoms at least 12 weeks after infection with severe acute respiratory syndrome coronavirus-2 that can be ascribed to the infection, in patients surviving coronavirus disease 2019 (COVID-19) Symptom ongoing at >12 weeks after COVID-19

Total number of patients

n (%)

Admitted

n (%)

Not admitted

n (%)

Number of patients 37 20 (54) 17 (46) Meeting criteria for post-COVID-19 syndrome 19 (51) 14 (70) 5 (29) Shortness of breath 14 (38) 12 (60) 2 (12) Cough 5 (14) 2 (10) 3 (18) Fatigue 14 (38) 11 (55) 3 (18) Muscle ache 1 (3) 1 (5) 0 Depression or anxiety 6 (16) 5 (25) 1 (6) Anosmia 3 (8) 2 (10) 1 (6) Rash 2 (5) 0 2 (12) Hair loss 1 (3) 1 (5) 0 Fever 0 0 0 Abdominal pain 0 0 0 Diarrhoea 0 0 0

Outcomes for patients with haematological disorders who survived infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Each horizontal bar represents one surviving patient, with the colour denoting presence (yellow bar) versus absence (green bar) of ongoing symptoms that can be attributed to coronavirus disease 2019 (COVID-19) at >12 weeks after infection. There is no correlation between age of surviving patients with post-COVID-19 syndrome (mean [SD] 65·9 [13] years), compared with those without this syndrome (mean [SD] 65·9 [16] years) (p = 0·99 using Welch t-test)

The World Health Organization (WHO) clinical progression scale8 was retrospectively calculated for all patients at the peak of their acute infection (Table 3). In surviving patients, a higher score on this scale correlated with risk of meeting the criteria for post-COVID-19 syndrome.

TABLE 3. World Health Organization (WHO) Clinical Progression Scale at peak of acute infection, and number of patients that later meet criteria for post-coronavirus disease 2019 (COVID-19) syndrome WHO clinical progression scale Total number of patients With post-COVID-19 syndrome, n (%) Without post-COVID-19 syndrome, n (%) 1. Asymptomatic 0 0 0 2. Symptomatic, independent 12 2 (17) 10 (83) 3. Symptomatic needing assistance 5 2 (40) 3 (60) 4. Hospitalised, no supplementary oxygen 7 2 (29) 5 (71) 5. Hospitalised – nasal oxygen 8 6 (75) 2 (25) 6. Hospitalised – non-invasive ventilation 5 5 (100) 0 7–9. Intubated and ventilated 0 0 0 10. Dead 28 – –

The frequency of post-COVID-19 syndrome in this population of patients with underlying haematological diagnoses (51%) is markedly higher than has been reported in the general population, although the distribution of the ongoing symptoms is very similar.2, 4

DISCUSSION

Importantly, unlike the risk of death, which is heavily correlated with older age, there was no correlation of age with the risk of post-COVID-19 syndrome (Figure 2). A correlation was found between the length of hospital stay and the persistence of ongoing symptoms (p = 0·005), but importantly, 29% of patients with post-COVID-19 syndrome in the present cohort were never admitted to hospital.

There was no significant correlation between whether patients had active disease (p = 0·81), were currently on chemotherapy (p = 0·47), had had previous chemotherapy (p = 0·73), or had had previous treatment with a CD20-targetting agent (p = 0·26), and the risk of developing post-COVID-19 syndrome.

The high prevalence of persistent symptoms following COVID-19 will pose additional challenges for clinicians, who will need to consider whether symptoms relate to previous therapies or worsening of comorbidities, may represent a progression of the underlying haematological disorder, or rather sequelae to SAR-CoV-2 infection. The lack of diagnostic tests to confirm post-COVID-19 syndrome, the diversity of reported symptoms,9 and the lack of a clear pathway for treatment further complicate management. A careful history is likely to be the most important means of assessing symptoms, as symptoms relating to post-COVID-19 syndrome will have a clear onset with infection and will typically improve slowly with time, whereas progressive haematological disease will typically slowly worsen. This cohort study is not large enough and has an insufficient follow-up period to assess the impact of post-COVID-19 syndrome on the ongoing treatment and activity of the underlying haematological disorder, but this will be an important subject for future study.

Although this study is limited by its small sample size, and further research is required to investigate these findings and their applicability to larger populations, a strength is that all possible measures were taken to identify and include every patient with a haematological disease to have contracted SARS-CoV-2 within the catchment of our hospital. Patients were prospectively sought as the pandemic progressed and both hospitalised and non-hospitalised patients were included.

CONCLUSION

Post-COVID-19 syndrome is potentially under-recognised in patients with haematological disorders. This study suggests that it may be more common than is seen in the general population and clinicians should consider this as a cause of worsening symptoms in patients known to had COVID-19. The likelihood of developing post-COVID-19 syndrome does not appear to be linked to the age of the patient, with young and old patients equally affected. It is more common in those who were admitted to hospital for treatment of COVID-19 but is also frequent in those who had not required hospitalisation.

We recommend that colleagues consider establishing a post-COVID-19 clinic specifically for this patient group, in order to pro-actively identify patients with persistent symptoms, as specialist referrals may aid their recovery.

REFERENCES

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