The COVID-19 infection has been declared a global emergency affecting 0.7% of the 7.8 billion worldwide human population, with the burden still growing [1]. The disease is causing revolutionary changes in personal lifestyle, health care systems and socio-economic distributions. In spite of universal precautions adopted to prevent this infection in the HD community, the incidence of this novel viral infection remains high among HD patients. This systematic review and meta-analysis of 29 international studies, including 3261 confirmed COVID-19 cases, drawn from a pool of 396,062 HD patients, found that the incidence of COVID-19 infection was 7.7% and the mortality rate was 22.4%, i.e. higher than in the general population. Understanding of incidence, clinical presentation and mortality related to COVID-19 in HD patients may help to design appropriate interventions for prevention, timely diagnosis and treatment of this global challenge in this vulnerable population.
HD patients are more susceptible to COVID-19 infection because of greater age, coexistence of multiple comorbidities, relatively immune-suppressed status and factors related to the scheduled renal replacement sessions constituting their lifelong treatment [13, 14]. Necessary, frequent visits to areas of high population density (public transportation or HD facilities) and close personal contacts (with medical-, nursing- or caregiver staff) make effective strategies to prevent viral infection, such as social distancing or stay-home orders, difficult to implement for this select population of patients [14]. Accordingly, a 15.4-fold increase was noted in the incidence of COVID-19 in our study, with patients also being older, compared to the general population [13]. The mean ages of patients were slightly greater (63.5 years) in patients of non-Asian studies than those of Asian studies (61.8 years). Variations in both criteria for viral screening and confirmatory methods of COVID-19 infection may also explain the difference in the incidence observed between studies of the two geographic areas. The difference in incidence observed between Asian and non-Asian populations may be greater than expected. Asian countries adopted universal screening using a nucleic acid test, serology or computed tomography. The serologic antibody response is detectable 7 to 10 days or later after the onset of symptoms of COVID-infection in the general population [15]; however, the humoral response may extend from 14 to 55 days in HD patients [16]. By contrast, non-Asian countries, except for Canada [17], conducted viral screening only in symptomatic patients or patients at high risk of exposure, using mainly nucleic acid test. The latter approach may mitigate the overwhelming burden on testing facilities; however, subclinical cases increase the difficulty of identifying COVID-19 infected HD patients and controlling outbreaks in the dialysis centers, and may lead to underestimation of the exact incidence of COVID-19 infection in asymptomatic HD patients. Manganos et al, at a very early stage of the disease outbreak, used radiographic signs suggestive of interstitial pneumonia as surrogate criteria for COVID-19 disease [18]. A nationwide serology screening involving 28,503 HD patients in the US found that seroprevalence was 8.3%, standardizing with the US dialysis population [19]; however, serology data were largely un-reported in non-Asian studies. All these differences may confer heterogeneity to the global incidence observed in the HD population.
COVID-19 related mortality estimates range from 1.4–8% in the general population and are higher (25.5–39%) in hospitalized patients [2, 3, 20–22]. The prognosis of HD patients with COVID-19 is still unclear. We found overall mortality of 22.4% in HD patients infected with COVID-19. Previous literature has indicated several risk factors for high mortality in HD, including greater age, male gender, underlying cardiac or pulmonary disease, diabetes and hypertension and the use of mechanical ventilation [13, 14, 23]. Cough was associated with risk of mortality in French and Italian HD patients [24, 25]. Fever also predicted mortality in an Italian HD cohort [14]. Other prognostic factors have included dialysis vintage, thrombocytopenia, lymphopenia and increased LDH or CRP level [14, 22, 24]. However, most studies have reported less severe clinical symptoms in HD patients compared with the general population [22, 26, 27, 28]. In a Chinese series, the most common symptoms were fever, cough and bilateral ground-glass or patchy opacity of the lungs [16]. However, a retrospective Chinese study comparing 49 HD vs 52 non-renal failure patients having similar baseline characteristics found that fever, fatigue and dry cough were more predominant in controls, but less frequent in HD infected patients. In this series, fatigue and anorexia were the most common symptoms among HD infected patients [29]. In addition, 25% of infected patients confirmed by nucleic acid test and 79% of those identified by serologic testing were asymptomatic during the whole clinical course [16]. Further large prospective studies, including different ethnicities, should be conducted to inform risk stratification with the ultimate goal of improving the outcome of HD patients with COVID-19 infection.
This viral infection can trigger severe immune cytokine storm and the respiratory failure secondary to ARDS represents the leading cause of mortality [30]. Increased serum concentration of interleukin (IL)-2, IL-6, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein-1, macrophage inflammatory protein 1-α, tumor necrosis factor (TNF)-α and ferritin have been observed in individuals infected with COVID-19 [30, 31]. This hyper-inflammatory storm may play an important role in the tissue damage and death of patients [4, 32]; however, this response is blunted in infected HD patients. Several studies have revealed leukopenia, lymphopenia, lower serum calcium concentration and elevated CRP levels in HD patients; however, several other researchers have failed to find changes in numbers of granulocytes or lymphocytes in infected HD patients [16, 26, 29, 33, 34]. Ma Y et al. found that the counts of T cells, CD4 T cells, CD8 T cells, natural killer cells, and B lymphocytes were reduced in the peripheral blood of infected HD patients compared with non-HD patients. In contrast, the serum levels of IL-4, IL-6, IL-10, interferon-γ and TNF-α were lowest in infected HD patients, compared to non-infected HD patients or COVID-19 infected patients with normal renal function [27]. Further evidence of attenuated cytokine reaction in HD patients could be manifest in the low proportion of ARDS reported in various studies. Our meta-analysis indicated an overall incidence of ARDS of 18.5%, significantly lower than the reported incidence from hospitalized patients (33%) [35]. It is unknown whether the immuno-compromised status per se, or the hemodiafiltration/hemoperfusion may have facilitated cytokine clearance. Although these findings may prove beneficial for patient survival they also imply protracted duration in eliminating the virus and hence persistent shedding in HD patients, which must be considered from a public health perspective. Studies investigating the dynamics of viral load in HD patients remain limited. Appropriate duration for quarantine or treatment course should be designed in future trials to avoid inadvertent transmission of COVID-19 among HD patients.
Again, studies among HD patients from Asian countries have reported lower mortality (17.0%) than from non- Asian countries (26.7%). Asian patients are more likely to be young and have milder clinical presentation than their non-Asian counterparts. The ubiquitous deployment of CT scan, especially in China, may have allowed better detection of severe lung condition feasible to timely intervention [33]. The optimal antiviral therapy for HD patients is largely unknown. Current consensus recommends the use of antiviral therapy in the first stage for viral clearance, followed up by immune-suppressive strategies (for example with glucocorticoids or anti-cytokine drugs) to ameliorate cytokine injury [36]. Combinations of antibiotics or Chinese herbal medicine administrations were observed in Chinese studies [26, 29, 34]. Further randomized controlled trials comparing effectiveness and safety of different therapies should be undertaken in HD patients.
The findings of our study have several implications for clinical practice and also preventive medicine. The high incidence, with indolent or even asymptomatic clinical course may prevent timely identification of infected patients and may result in extensive spreading of virus in the crowded and highly-loaded medical area. Universal testing to stop the dissemination of COVID-19 should be leveraged with the appropriate testing capacity. For infected HD patients, cautions regarding prolonged viral shedding and prudence in the use of immuno-suppressive agents should be considered, taking into account the blunted immune reaction of HD patients. Ultimately, given the multiple coexistent high-risk conditions, vaccination, if proven safe, should be prioritized for HD patients.
The results of our study provide a panoramic understanding of COVID19 infection in HD patients. However, several limitations should be addressed. First, COVID-19 infection is unlikely to be eliminated in the near future, and more studies related to the epidemiology in HD patients with COVID-19 infection will be published after the presented work. Therefore, regularly updated systematic review and meta-analysis is suggested to confirm our findings. Second, all included studies report mortality with COVID-19 infection in HD patients after short follow-up periods, while the long-term outcomes in this population are yet to be determined. Third, we could not derive all the important information from the included studies, even if we did contact the study authors for those data. To reduce the effect of possible reporting bias on our result estimates, we conducted subgroup analyses using the study quality, which showed similar findings to the overall analyses. Finally, we included studies reporting data of patients receiving in-center HD treatment. Data of dialysis patients undergoing different modalities, such as home hemodialysis or peritoneal dialysis, remain unknown. We suggest the introduction of a standardized international registry of COVID-19 infected dialysis patients to collect detailed patient characteristics and prognosis data, which would be beneficial for the fight against the current pandemic and for the further development of optimal management for dialysis patients.