Published 20 January 2021
Hundreds of articles have been published over the last twelve months, making well-meaning attempts to determine whether patients with different co-morbidities are more susceptible for SARS-CoV-2 infection or at higher risk for severe disease. This deluge of scientific publications has resulted in worldwide uncertainty. For a number of reasons, many studies must be interpreted with extreme caution.
First, in many articles, the number of patients with specific co-morbidities is low. Small sample sizes preclude accurate comparison of COVID-19 risk between these patients and the general population. They may also overestimate mortality, especially if the observations were made in-hospital (reporting bias). Moreover, the clinical manifestation and the relevance of a condition may be heterogeneous. Is the hypertension treated or untreated? What is the stage of the COPD, only mild or very severe with low blood oxygen levels? Is the “cancer” cured, untreated or actively being treated? Are we talking about a seminoma cured by surgical orchiectomy years ago or about palliative care for pancreatic cancer? What is a “former” smoker: someone who decided to quit 20 years ago after a few months puffing during adolescence or someone with 40 package-years who stopped the day before his lung transplantation? Does “HIV” mean a well controlled infection while on long-lasting, successful antiretroviral therapy or an untreated case of AIDS? Unfortunately, many researchers tend to combine these cases, in order to get larger numbers and to get their paper published.
Second, there are numerous confounding factors to consider. In some case series, only symptomatic patients are described, in others only those who were hospitalized (and who have per se a higher risk for severe disease). In some countries, every patient with SARS-CoV-2 infection will be hospitalized, in others only those with risk factors or with severe COVID-19. Testing policies vary widely between countries. The control group (with or without co-morbidities) is not always well-defined. Samples may not be representative, risk factors not correctly taken into account. Sometimes, there is incomplete information about age distribution, ethnicity, co-morbidities, smoking, drug use and gender (there is some evidence that, in female patients, co-morbidities have no or less impact on the course of the disease, compared to males (Meng 2020)). All these issues present important limitations and only a few studies have addressed all of them.
Third, co-morbidity papers have led to an information overload. Yes, virtually every medical discipline and every specialist has to cope with the current pandemic. And yes, everybody has to be alert these days, psychiatrists as well as esthetic surgeons. Hundreds of guidelines or position papers have been published, trying to thoughtfully balance fear of COVID-19 against the dire consequences of not treating other diseases than COVID-19 in an effective or timely manner – and all this in the absence of data. On May 15, a PubMed search yielded 530 guidelines or considerations about specific diseases in the context of COVID-19, among them those for grade IV glioma (Bernhardt 2020, bottom line: do not delay treatment), but also for dysphonia and voice rehabilitation (Mattei 2020: can be postponed), infantile hemangiomas (Frieden 2020: use telehealth), ocular allergy (Leonardi 2020: very controversial), high resolution anoscopy (Mistrangelo 2020: also controversial), migraine management (Szperka 2020: use telehealth) and breast reconstruction (Salgarello 2020: defer “whenever possible”), to name just a few. These recommendations are usually not helpful. They apply for a few weeks, during acute health crisis scenarios as seen in overwhelmed health care systems in Wuhan, Bergamo, Madrid or New York. In other cities or even a few weeks later, proposed algorithms are already outdated. Nobody needs a 60-page recommendation, concluding that “clinical judgment and decision making should be exercised on a case-by-case basis”.
However, some important papers have been published over the last months, a couple of them with very helpful data, supporting the management of patients with co-morbidities. In the following, we will briefly go through these.
From the beginning of the pandemic, hypertension and/or cardiovascular disease (CVD) have been identified as potential risk factors for severe disease and death (Table 1). However, all studies were retrospective, included only hospitalized patients and did not distinguish between uncontrolled and controlled hypertension or used different definitions for CVD. Multivariate analyses adjusting for confounders were performed in only a few studies. Moreover, different outcomes and patient groups were analyzed. According to some experts, current data do not necessarily imply a causal relationship between hypertension and severity of COVID-19. There is no study that demonstrates the independent predictive value of hypertension. It is “unclear whether uncontrolled blood pressure is a risk factor for acquiring COVID-19, or whether controlled blood pressure among patients with hypertension is or is not less of a risk factor” (Schiffrin 2020). The same applies to CVD, with the difference that the numbers here are even lower.
From a mechanistic point of view, however, it seems plausible that patients with underlying cardiovascular diseases and pre-existing damage to blood vessels such as artherosclerosis may face higher risks for severe diseases. During recent weeks, it has become clear that SARS-CoV-2 may directly or indirectly attack the heart, kidney and blood vessels. Various cardiac manifestations of COVID-19 do occur contemporarily in many patients (see chapter Clinical Presentation, page 293). Infection may lead to cardiac muscle damage, blood vessel constriction and to elevated levels of inflammation-inducing cytokines. These direct and indirect adverse effects of the virus may be especially deleterious in those with already established heart disease. During the next months, we will learn more about the role and contributions of arteriosclerosis in the pathogenesis of COVID-19.
|Table 1. Hypertension in larger cohort studies, prevalence and outcome|
|Study||Setting||Hypertension present?||Multivariate, hazard or odds ratio (95% CI) for endpoint|
|Wang 2020||344 ICU pts,
|Survivors vs Non-Survivors: 34 vs 52%||Not done|
|Grasselli 2020||521 ICU pts,
72 hospitals in Italy
|Discharge from ICU vs death at ICU: 40 vs 63%||Not done|
|Guan 2020||1099 hospitalized pts, 522 hospitals in China||Non-severe disease vs severe: 13 vs 24%||Not done|
|Zhou 2020||191 hospitalized pts from Jinyintan and Wuhan||Survivors vs Non-Survivors: 23 vs 48%||Not done|
|Shi 2020||487 hospitalized pts
in Zhejing Province
|Non-severe disease at admission vs severe:
17 vs 53%
|OR 2,7 (1,3-5,6) for severe disease at admission|
|Guan 2020||1590 hospitalized pts, 575 hospitals in China||Non-severe vs severe courses: 13 vs 33%||HR 1,6 (1,1-2,3) for severe course (ICU, IMV, death)|
|Goyal 2020||393 hospitalized pts,
2 hospitals in New York
|No IMV vs IMV during stay: 48 vs 54%||Not done|
IMV invasive mechanical ventilation, ICU intensive care units
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Treatment of hypertension during the pandemic
There has hardly been a topic that has kept doctors and their patients as busy as the question of whether antihypertensive drugs such as ACE inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) can cause harm to patients. The uncontrolled observations of increased mortality risk in patients with hypertension, CVD (see above) and diabetes raised concerns. These conditions share underlying renin-angiotensin-aldosterone system pathophysiology that may be clinically insightful. In particular, activity of the angiotensin-converting enzyme 2 (ACE2) is dysregulated (increased) in cardiovascular disease (Vaduganathan 2020). As SARS-CoV-2 cell entry depends on ACE2 (Hoffmann 2020), increased ACE2 levels may increase the virulence of the virus within the lung and heart.
There is a large study that examined the association between pre-infection blood pressure (BP) control and COVID-19 outcomes using data from 460 general practices in England (Sheppard 2020). Eligible patients were adults with hypertension who were diagnosed with COVID-19. A total of 4277 patients (9,4%) were diagnosed with COVID-19 and 877 died within 28 days. There was no association between BP control and COVID-19 diagnosis or hospitalization. Of note, individuals with stage 1 uncontrolled BP had lower odds of COVID-19 death (OR 0,76, 95%CI: 0,62-0,92) compared to patients with well-controlled BP. However, these patients were older, had more co-morbidities and had been diagnosed with hypertension for longer, suggesting more advanced atherosclerosis and target organ damage.
ACEIs or ARBs may alter ACE2, and variation in ACE2 expression may in part be responsible for disease virulence. However, the first substantial study to examine the association between plasma ACE2 concentrations and the use of ACEIs/ARBs did not support this hypothesis: in two large cohorts from the pre-COVID-19 era, plasma concentrations of ACE2 were markedly higher in men than in women, but not with ACEI/ARB use (Sama 2020). A recent review of 12 animal studies and 12 human studies overwhelmingly implies that administration of both drug classes does not increase ACE2 expression (Sriram 2020).
However, some concerns on deleterious effects continue and some media sources and even scientific papers have called for the discontinuation of these drugs. This is remarkable as almost no clinical study showed any evidence of harm.
- Among 2573 COVID-19 patients with hypertension from New York City, there were no differences in the likelihood for severe COVID-19 for different classes of antihypertensive medications – ACE inhibitors, ARBs, beta blockers, calcium channel blockers, and thiazide diuretics (Reynolds 2020).
- Comparing 6272 Italian cases (positive for SARS-CoV-2) to 30,759 controls (matched for sex, age, and municipality of residence), no evidence was found that ACE inhibitors or ARBs modify susceptibility to COVID-19 (Mancia 2020). The results applied to both sexes as well as to younger and older persons.
- In a retrospective study from Denmark (one of the countries with the best epidemiological data) of 4480 COVID-19 patients, prior ACEI/ARB use, compared with no use, was not significantly associated with mortality. In a nested case-control study of a cohort of 494.170 patients with hypertension, use of ACEI/ARB, compared with use of other antihypertensive medications, was not significantly associated with COVID-19 diagnosis (Fosbøl 2020).
- In a multicenter cohort study following more than 1,3 million patients with hypertension from the USA and Spain, no clear association of increased risk of COVID-19 diagnosis, hospital admission, or subsequent complications was seen with the outpatient use of ACEI or ARB. Furthermore, the marginal difference between ACEIs and ARBs does not warrant class switching (Morales 2020).
- Does discontinuation compared with continuation of ACEIs or ARBs change anything? No. In an open label RCT that included 659 patients from Brazil who were hospitalized with mild to moderate COVID-19 who were taking ACEIs or ARBs before hospital admission, the mean number of days alive and out of the hospital for those assigned to discontinue versus continue these medications was 21,9 vs 22,9, respectively (Lopes 2020).
In conclusion, ACE inhibitors and/or ARBs should not be discontinued. Several other RCT plan to evaluate ACEIs and ARBs for treatment of COVID-19 (Mackey 2020). According to a brief review, adjuvant treatment and continuation of pre-existing statin therapy could improve the clinical course of patients with COVID-19, either by their immunomodulatory action or by preventing cardiovascular damage (Castiglion 2020). In a retrospective study on 13.981 patients in Hubei Province, China, the use of statins was independently associated with lower all-cause mortality (5,2% vs 9,4%). However, an observational cohort study using data from Danish nationwide registries, 843/4842 (17%) COVID-19 patients redeemed a prescription of statins in the 6 months prior to COVID-19 diagnosis. Recent statin exposure was not associated with an increased or decreased risk of all-cause mortality or severe infection (Butt 2020). Randomized controlled trials involving statin treatment for COVID-19 are needed.
Pre-existing cardiovascular disease is linked with higher morbidity and mortality in patients with COVID-19, whereas COVID-19 itself can induce myocardial injury, arrhythmia, acute coronary syndrome and venous thromboembolism (nice review: Nishiga 2020). Myocardial injury, evidenced by elevated cardiac biomarkers, was recognized among early cases and myocardial infarction (STEMI or NSTEMI) and may represent the first clinical manifestation of COVID-19. Of note, a culprit lesion is often not identifiable by coronary angiography. In a study of 28 patients with STEMI, this was the case in 39% (Stefanini 2020). According to the authors, a dedicated diagnostic pathway should be delineated for COVID-19 patients with STEMI, aimed at minimizing procedural risks and healthcare providers’ risk of infection. There are already preliminary reports on a significant decline of 32% in the number of percutaneous coronary interventions for acute coronary syndromes (Piccolo 2020). Other authors have suggested that, in settings with limited resources to protect the work force, fibrinolytic therapies may be preferred over primary percutaneous coronary interventions (Daniels 2020).
In a meta-analysis, outcomes of 50.123 patients from 10 studies were assessed. Data showed that acute and timely medical care of these patients had been maintained during the pandemic in most countries. Consequently, despite a significant reduction in overall admission rates of patients with STEMI during the COVID-19 pandemic, there was no significant difference in hospital mortality compared with patients with STEMI admitted before the outbreak (Rattka).
Of note, several studies have found a spectacular drop in admissions for STEMI during the peak of the epidemic. In France a steep decline of 25% was found for both acute ( < 24hrs) and late presentation (> 24 hrs) STEMI (Rangé 2020). Similar observations have been made in Italy (De Filippo 2020) and the US (Solomon 2020). Possible explanations for this phenomenon may be patients’ fear of coming to the hospital or disturbing busy caregivers, especially in the case of mild STEMI clinical presentation. Other hypothetical reasons are reduced air pollution, better adherence to treatment, limited physical activity or absence of occupational stress during lockdown. However, there is some evidence that the lower incidence does not reflect a true decline but just one more collateral damage of the pandemic. For example, Italian researchers have found a 58% increase of out-of-hospital cardiac arrests in March 2020 compared to the same period in 2019 (Baldi 2020). In New York, this increase seemed to be even more pronounced (Lai 2020). Others have observed an increased observed/expected mortality ratio during the early COVID-19 period indicating that patients try to avoid hospitalization (Gluckman 2020).
Baldi E, Sechi GM, Mare C, et al. Out-of-Hospital Cardiac Arrest during the Covid-19 Outbreak in Italy. N Engl J Med. 2020 Apr 29. PubMed: https://pubmed.gov/32348640. Full-text: https://doi.org/10.1056/NEJMc2010418
Bernhardt D, Wick W, Weiss SE, et al. Neuro-oncology Management During the COVID-19 Pandemic With a Focus on WHO Grade III and IV Gliomas. Neuro Oncol. 2020 May 5;22(7):928-35. PubMed: https://pubmed.gov/32369601. Full-text: https://doi.org/10.1093/neuonc/noaa113
Butt JH, Gerds TA, Schou M, et al. Association between statin use and outcomes in patients with coronavirus disease 2019 (COVID-19): a na-tionwide cohort study. BMJ Open. 2020 Dec 4;10(12):e044421. Pub-Med: https://pubmed.gov/33277291. Full-text: https://doi.org/10.1136/bmjopen-2020-044421
Castiglione V, Chiriacò M, Emdin M, Taddei S, Vergaro G. Statin therapy in COVID-19 infection. Eur Heart J Cardiovasc Pharmacother. 2020 Jul 1;6(4):258-259. PubMed: https://pubmed.gov/32347925. Full-text: https://doi.org/10.1093/ehjcvp/pvaa042
Daniels MJ, Cohen MG, Bavry AA, Kumbhani DJ. Reperfusion of STEMI in the COVID-19 Era – Business as Usual? Circulation. 2020 Apr 13. PubMed: https://pubmed.gov/32282225. Full-text: https://doi.org/10.1161/CIRCULATIONAHA.120.047122
De Filippo O, D’Ascenzo F, Angelini F, et al. Reduced Rate of Hospital Admissions for ACS during Covid-19 Outbreak in Northern Italy. N Engl J Med. 2020 Jul 2;383(1):88-89. PubMed: https://pubmed.gov/32343497. Full-text: https://doi.org/10.1056/NEJMc2009166
Fosbøl EL, Butt JH, Østergaard L, et al. Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With COVID-19 Diagnosis and Mortality. JAMA. 2020 Jul 14;324(2):168-177. PubMed: https://pubmed.gov/32558877. Full-text: https://doi.org/10.1001/jama.2020.11301
Frieden IJ, Puttgen KB, Drolet BA, et al. Management of Infantile Hemangiomas during the COVID Pandemic. Pediatr Dermatol. 2020 Apr 16. PubMed: https://pubmed.gov/32298480. Full-text: https://doi.org/10.1111/pde.14196
Gluckman TJ, Wilson MA, Chiu ST, et al. Case Rates, Treatment Approaches, and Outcomes in Acute Myocardial Infarction During the Coronavirus Disease 2019 Pandemic. JAMA Cardiol. 2020 Aug 7:e203629. PubMed: https://pubmed.gov/32766756. Full-text: https://doi.org/10.1001/jamacardio.2020.3629
Goyal P, Choi JJ, Pinheiro LC, et al. Clinical Characteristics of Covid-19 in New York City. N Engl J Med. 2020 Apr 17. PubMed: https://pubmed.gov/32302078. Full-text: https://doi.org/10.1056/NEJMc2010419
Grasselli G, Zangrillo A, Zanella A, et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020 Apr 6. pii: 2764365. PubMed: https://pubmed.gov/32250385. Full-text: https://doi.org/10.1001/jama.2020.5394
Guan WJ, Liang WH, Zhao Y, et al. Co-morbidity and its impact on 1590 patients with Covid-19 in China: A Nationwide Analysis. Eur Respir J. 2020 Mar 26. PubMed: https://pubmed.gov/32217650. Full-text: https://doi.org/10.1183/13993003.00547-2020
Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Feb 28. PubMed: https://pubmed.gov/32109013. Full-text: https://doi.org/10.1056/NEJMoa2002032
Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 Mar 4. PubMed: https://pubmed.gov/32142651. Full-text: https://doi.org/10.1016/j.cell.2020.02.052
Lai PH, Lancet EA, Weiden MD, et al. Characteristics Associated With Out-of-Hospital Cardiac Arrests and Resuscitations During the Novel Coronavirus Disease 2019 Pandemic in New York City. JAMA Cardiol. 2020 Jun 19;5(10):1154-63. PubMed: https://pubmed.gov/32558876. Full-text: https://doi.org/10.1001/jamacardio.2020.2488
Leonardi A, Fauquert JL, Doan S, et al. Managing ocular allergy in the time of COVID-19. Allergy. 2020 Sep;75(9):2399-2402. PubMed: https://pubmed.gov/32402114. Full-text: https://doi.org/10.1111/all.14361
Lopes RD, Macedo AV, Silva P, et al. Effect of Discontinuing vs Continu-ing Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Re-ceptor Blockers on Days Alive and Out of the Hospital in Patients Admitted With COVID-19: A Randomized Clinical Trial. JAMA January 19, 2021; 325(3):254-264. doi: 10.1001/jama.2020.25864
Mackey K, Kansagara D, Vela K. Update Alert 2: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults. Ann Intern Med. 2020 Jul 23. PubMed: https://pubmed.gov/32701362. Full-text: https://doi.org/10.7326/L20-0969
Mancia G, Rea F, Ludergnani M, Apolone G, Corrao G. Renin-Angiotensin-Aldosterone System Blockers and the Risk of Covid-19. N Engl J Med. 2020 Jun 18;382(25):2431-2440. PubMed: https://pubmed.gov/32356627. Full-text: https://doi.org/10.1056/NEJMoa2006923
Mattei A, Amy de la Bretèque B, Crestani S, et al. Guidelines of clinical practice for the management of swallowing disorders and recent dysphonia in the context of the COVID-19 pandemic. Eur Ann Otorhinolaryngol Head Neck Dis. 2020 May;137(3):173-175. PubMed: https://pubmed.gov/32332004. Full-text: https://doi.org/10.1016/j.anorl.2020.04.011
Meng Y, Wu P, Lu W, et al. Sex-specific clinical characteristics and prognosis of coronavirus disease-19 infection in Wuhan, China: A retrospective study of 168 severe patients. PLoS Pathog. 2020 Apr 28;16(4):e1008520. PubMed: https://pubmed.gov/32343745. Full-text: https://doi.org/10.1371/journal.ppat.1008520. eCollection 2020 Apr
Mistrangelo M, Naldini G, Morino M. Do we really need guidelines for HRA during COVID-19 pandemic? Colorectal Dis. 2020 May 7. PubMed: https://pubmed.gov/32379928. Full-text: https://doi.org/10.1111/codi.15116
Morales DR, Conover MM, You SC, et al. Renin–angiotensin system blockers and susceptibility to COVID-19: an international, open science, cohort analy-sis. Lancet Digital Health December 17, 2020. Full-text: https://doi.org/10.1016/S2589-7500(20)30289-2
Nishiga M, Wang DW, Han Y, Lewis DB, Wu JC. COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives. Nat Rev Cardiol. 2020 Sep;17(9):543-558. PubMed: https://pubmed.gov/32690910. Full-text: https://doi.org/10.1038/s41569-020-0413-9
Piccolo R, Bruzzese D, Mauro C, et al. Population Trends in Rates of Percutaneous Coronary Revascularization for Acute Coronary Syndromes Associated with the COVID-19 Outbreak. Circulation. 2020 Apr 30. PubMed: https://pubmed.gov/32352318. Full-text: https://doi.org/10.1161/CIRCULATIONAHA.120.047457
Rangé G, Hakim R, Motreff P. Where have the ST-segment elevation myocardial infarctions gone during COVID-19 lockdown? Eur Heart J Qual Care Clin Outcomes. 2020 Jul 1;6(3):223-224. PubMed: https://pubmed.gov/32348457. Full-text: https://doi.org/10.1093/ehjqcco/qcaa034
Rattka M, Dreyhaupt J, Winsauer C, et al. Effect of the COVID-19 pandemic on mortality of patients with STEMI: a systematic review and meta-analysis. Heart. 2020 Dec 17:heartjnl-2020-318360. PubMed: https://pubmed.gov/33334863. Full-text: https://doi.org/10.1136/heartjnl-2020-318360
Reynolds HR, Adhikari S, Pulgarin C, et al. Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19. N Engl J Med. 2020 May 1. PubMed: https://pubmed.gov/32356628. Full-text: https://doi.org/10.1056/NEJMoa2008975
Salgarello M, Adesi LB, Visconti G, Pagliara DM, Mangialardi ML. Considerations for performing immediate breast reconstruction during the COVID-19 pandemic. Breast J. 2020 May 7. PubMed: https://pubmed.gov/32383321. Full-text: https://doi.org/10.1111/tbj.13876
Sama IE, Ravera A, Santema BT, et al. Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors. Eur Heart J. 2020 May 14;41(19):1810-1817. PubMed: https://pubmed.gov/32388565. Full-text: https://doi.org/10.1093/eurheartj/ehaa373
Schiffrin EL, Flack J, Ito S, Muntner P, Webb C. Hypertension and COVID-19. Am J Hypertens. 2020 Apr 6. pii: 5816609. PubMed: https://pubmed.gov/32251498. Full-text: https://doi.org/10.1093/ajh/hpaa057
Sheppard JP, Nicholson B, Lee J, et al. The association between blood pres-sure control and Coronavirus Disease 2019 outcomes in 45,418 symptomatic patients with hypertension: An observational cohort study. Hypertension. 2020 Dec 16. PubMed: https://pubmed.gov/33325240. Full-text: https://doi.org/10.1161/HYPERTENSIONAHA.120.16472
Shi Y, Yu X, Zhao H, Wang H, Zhao R, Sheng J. Host susceptibility to severe COVID-19 and establishment of a host risk score: findings of 487 cases outside Wuhan. Crit Care. 2020 Mar 18;24(1):108. PubMed: https://pubmed.gov/32188484. Full-text: https://doi.org/10.1186/s13054-020-2833-7
Solomon MD, McNulty EJ, Rana JS, et al. The Covid-19 Pandemic and the Incidence of Acute Myocardial Infarction. N Engl J Med. 2020 Aug 13;383(7):691-693. PubMed: https://pubmed.gov/32427432. Full-text: https://doi.org/10.1056/NEJMc2015630
Stefanini GG, Montorfano M, Trabattoni D, et al. ST-Elevation Myocardial Infarction in Patients with COVID-19: Clinical and Angiographic Outcomes. Circulation. 2020 Apr 30. PubMed: https://pubmed.gov/32352306. Full-text: https://doi.org/10.1161/CIRCULATIONAHA.120.047525
Szperka CL, Ailani J, Barmherzig R, et al. Migraine Care in the Era of COVID-19: Clinical Pearls and Plea to Insurers. Headache. 2020 May;60(5):833-842. PubMed: https://pubmed.gov/32227596. Full-text: https://doi.org/10.1111/head.13810
Wang Y, Lu X, Chen H, et al. Clinical Course and Outcomes of 344 Intensive Care Patients with COVID-19. Am J Respir Crit Care Med. 2020 Apr 8. PubMed: https://pubmed.gov/32267160. Full-text: https://doi.org/10.1164/rccm.202003-0736LE
Zhang XJ, Qin JJ, Cheng X, et al. In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19. Cell Metab. 2020 Aug 4;32(2):176-187.e4. PubMed: https://pubmed.gov/32592657. Full-text: https://doi.org/10.1016/j.cmet.2020.06.015
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 11. PubMed: https://pubmed.gov/32171076. Full-text: https://doi.org/10.1016/S0140-6736(20)30566-3
Diabetes mellitus is a chronic inflammatory condition characterized by several macrovascular and microvascular abnormalities. As with hypertension and CVD, many of the above cited studies have also revealed that diabetic patients were overrepresented among the most severely ill patients with COVID-19 and those succumbing to the disease. Among the 23,698 in-hospital COVID-19-related deaths during the first months in the UK, a third occurred in people with diabetes: 7,434 (31.4%) in people with type 2 diabetes, 364 (1.5%) in those with type 1 diabetes (Barron 2020).
Current data suggest that diabetes in patients with COVID-19 is associated with a two-fold increase in mortality as well as severity of COVID-19, as compared to non-diabetics. In a meta-analysis of 33 studies and 16.003 patients (Kumar 2020), diabetes was found to be significantly associated with mortality from COVID-19 with a pooled odds ratio of 1.90 (95% CI: 1,37-2,64). Diabetes was also associated with severe COVID-19 and a pooled odds ratio of 2.75 (95% CI: 2,09-3,62). The pooled prevalence of diabetes in patients with COVID-19 was 9,8% (95% CI: 8,7%-10,9%). However, it is too early to say whether diabetes is acting as an independent factor responsible for COVID severity and mortality or if it is just a confounding factor.
A large retrospective study on the impact of type 2 diabetes (T2D) carefully analyzed 7337 cases of COVID-19 in Hubei Province, China, among them 952 with pre-existing T2D (Zhu 2020). The authors found that subjects with T2D required more medical interventions and had a significantly higher mortality (7,8% versus 2,7%; adjusted hazard ratio, 1,49) and multiple organ injury than non-diabetic individuals. Of note, well-controlled blood glucose was associated with markedly lower mortality (in-hospital death rate 1,1% versus 11,0%) compared to individuals with poorly controlled blood glucose. Similar results were found in a large UK cohort (Holman 2020).
A recent review has made some suggestions on the possible pathophysiological mechanisms of the relationship between diabetes and COVID-19, and its management (Hussain 2020). Rigorous glucose monitoring and careful consideration of drug interactions might attenuate worsening of symptoms and adverse outcomes. In a retrospective cohort study of 1213 hospitalized individuals with COVID-19 and pre-existing T2D, metformin use was significantly associated with a higher incidence of acidosis, particularly in cases with severe COVID-19, but not with 28-day COVID-19-related mortality (Cheng 2020).
Some treatment strategies for COVID-19 such as steroids and lopinavir/r bear a risk for hyperglycemia. On the other hand, hydroxychloroquine may improve glycemic control in decompensated, treatment-refractory patients with diabetes (Gerstein 2002, Rekedal 2010). However, it remains unclear which COVID-19 treatment strategy works best and if treatment of diabetic patients has to be different from those without diabetes. It is also unclear whether specific diabetes drugs such as DPP4 inhibitors increase or decrease the susceptibility or severity of SARS-CoV-2 infection.
Isolated reports of new-onset diabetes in COVID-19 cases have also led to the hypothesis that SARS-CoV-2 is directly cytotoxic to pancreatic islet β cells. However, a careful investigation (Coate 2020) suggested that the interaction of diabetes and SARS-CoV-2 is mediated by systemic inflammation and/or metabolic changes in other organs such as liver, muscle or adipose tissue (and not by a direct infection of β cells in the pancreas).
Barron E, Bakhai C, Kar P, et al. Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study. Lancet Diabetes Endocrinol. 2020 Oct;8(10):813-822. PubMed: https://pubmed.gov/32798472. Full-text: https://doi.org/10.1016/S2213-8587(20)30272-2
Cheng X, Liu YM, Li H, et al. Metformin Is Associated with Higher Incidence of Acidosis, but Not Mortality, in Individuals with COVID-19 and Pre-existing Type 2 Diabetes. Cell Metab. 2020 Oct 6;32(4):537-547.e3. PubMed: https://pubmed.gov/32861268. Full-text: https://doi.org/10.1016/j.cmet.2020.08.013
Coate KC, Cha , Shrestha S. SARS-CoV-2 Cell Entry Factors ACE2 and TMPRSS2 are Expressed in the Microvasculature and Ducts of Human Pancreas but are Not Enriched in β Cells. Cell Metabolism November 13, 2020. Full-text: https://doi.org/10.1016/j.cmet.2020.11.006
Gerstein HC, Thorpe KE, Taylor DW, Haynes RB. The effectiveness of hydroxychloroquine in patients with type 2 diabetes mellitus who are refractory to sulfonylureas–a randomized trial. Diabetes Res Clin Pract. 2002 Mar;55(3):209-19. PubMed: https://pubmed.gov/11850097. Full-text: https://doi.org/10.1016/s0168-8227(01)00325-4
Holman N, Knighton P, Kar P, et al. Risk factors for COVID-19-related mortality in people with type 1 and type 2 diabetes in England: a population-based cohort study. Lancet Diabetes Endocrinol. 2020 Oct;8(10):823-833. PubMed: https://pubmed.gov/32798471. Full-text: https://doi.org/10.1016/S2213-8587(20)30271-0
Hussain A, Bhowmik B, do Vale Moreira NC. COVID-19 and diabetes: Knowledge in progress. Diabetes Res Clin Pract. 2020 Apr;162:108142. PubMed: https://pubmed.gov/32278764. Full-text: https://doi.org/10.1016/j.diabres.2020.10814
Kumar A, Arora A, Sharma P, et al. Is diabetes mellitus associated with mortality and severity of COVID-19? A meta-analysis. Diabetes Metab Syndr. 2020 May 6;14(4):535-545. PubMed: https://pubmed.gov/32408118. Full-text: https://doi.org/10.1016/j.dsx.2020.04.044
Rekedal LR, Massarotti E, Garg R, et al. Changes in glycosylated hemoglobin after initiation of hydroxychloroquine or methotrexate treatment in diabetes patients with rheumatic diseases. Arthritis Rheum. 2010 Dec;62(12):3569-73. PubMed: https://pubmed.gov/20722019. Full-text: https://doi.org/10.1002/art.27703
Zhu L, She ZG, Cheng X, et al. Association of Blood Glucose Control and Outcomes in Patients with COVID-19 and Pre-existing Type 2 Diabetes. Cell Metab. 2020 Jun 2;31(6):1068-1077.e3. PubMed: https://pubmed.gov/32369736. Full-text: https://doi.org/10.1016/j.cmet.2020.04.021
Chronic Obstructive Pulmonary Disease (COPD) is a common and preventable dysfunction of the lung associated with limitation in airflow. It is a complex disease associated with abnormalities of the airway and/or alveoli which is predominantly caused by exposure to noxious gases and particulates over a long period. A meta-analysis of 15 studies, including a total of 2473 confirmed COVID-19 cases showed that COPD patients were at a higher risk of more severe disease (calculated RR 1,88) and with 60% higher mortality (Alqahtani 2020). Unfortunately, the numbers in this review were very small and only 58 (2,3%) had COPD.
A meta-analysis of 5 early studies comprising 1399 patients observed only a trend but no significant association between active smoking and severity of COVID-19 (Lippi 2020). However, other authors have emphasized that current data do not allow to draw firm conclusions about the association of severity of COVID-19 with smoking status (Berlin 2020). In a more recent review, current smokers were 1.45 times more likely to have severe complications compared to former and never smokers. Current smokers also had a higher mortality rate (Alqahtani 2020).
Ever-smoking increased pulmonary ACE2 expression by 25% (Cai 2020). The significant smoking effect on ACE2 pulmonary expression may suggest an increased risk for viral binding and entry of SARS-CoV-2 into the lungs of smokers. Cigarette smoke triggers an increase in ACE2 positive cells by driving secretory cell expansion (Smith 2020). The overabundance of ACE2 in the lungs of smokers may partially explain a higher vulnerability of smokers.
However, it’s not that easy – both quitting smoking and finding clinical correlations to the above cell experiments. Within a surveillance center primary care sentinel network, multivariate logistic regression models were used to identify risk factors for positive SARS-CoV-2 tests (Lusignan 2020). Of note, active smoking was associated with decreased odds (yes, decreased: adjusted OR 0,49, 95% CI; 0,34–0,71). According to the authors, their findings should not be used to conclude that smoking prevents SARS-CoV-2 infection, or to encourage ongoing smoking. Several explanations are given, such as selection bias (smokers are more likely to have a cough, more frequent testing could increase the proportion of smokers with negative results). Active smoking might also affect RT-PCR test sensitivity.
Alqahtani JS, Oyelade T, Aldhahir AM, et al. Prevalence, Severity and Mortality associated with COPD and Smoking in patients with COVID-19: A Rapid Systematic Review and Meta-Analysis. PLoS One. 2020 May 11;15(5):e0233147. PubMed: https://pubmed.gov/32392262. Full-text: https://doi.org/10.1371/journal.pone.0233147
Cai G, Bosse Y, Xiao F, Kheradmand F, Amos CI. Tobacco Smoking Increases the Lung Gene Expression of ACE2, the Receptor of SARS-CoV-2. Am J Respir Crit Care Med. 2020 Apr 24. PubMed: https://pubmed.gov/32329629. Full-text: https://doi.org/10.1164/rccm.202003-0693LE
de Lusignan S, Dorward J, Correa A, et al. Risk factors for SARS-CoV-2 among patients in the Oxford Royal College of General Practitioners Research and Surveillance Centre primary care network: a cross-sectional study. Lancet Infect Dis. 2020 Sep;20(9):1034-1042. PubMed: https://pubmed.gov/32422204. Full-text: https://doi.org/10.1016/S1473-3099(20)30371-6
Lippi G, Henry BM. Active smoking is not associated with severity of coronavirus disease 2019 (COVID-19). Eur J Intern Med. 2020 Mar 16. PubMed: https://pubmed.gov/32192856. Full-text: https://doi.org/10.1016/j.ejim.2020.03.014
Smith JC, Sausville EL, Girish V, et al. Cigarette Smoke Exposure and Inflammatory Signaling Increase the Expression of the SARS-CoV-2 Receptor ACE2 in the Respiratory Tract. Dev Cell. 2020 Jun 8;53(5):514-529.e3. PubMed: https://pubmed.gov/32425701. Full-text: https://doi.org/10.1016/j.devcel.2020.05.012
HIV infection is of particular interest in the current crisis. First, many patients take antiretroviral therapies that are thought to have some effect against SARS-CoV-2. Second, HIV serves as a model of cellular immune deficiency. Third, and by far the most important point, the collateral damage caused by COVID-19 in the HIV population may be much higher than that of COVID-19 itself.
Preliminary data suggest no elevated incidence of COVID-19. In 5700 patients from New York, only 43 (0,8%) were found to be HIV-positive (Richardson 2020). In Barcelona, the standardized incidence rate was lower in persons living with HIV (PLWH) than in the general population (Inciarte 2020). Given the fact that HIV+ patients may be at higher risk for other infectious diseases such as STDs, these percentages were so low that some experts have already speculated on potential “protective” factors (i.e., antiviral therapies or immune activation). Moreover, a defective cellular immunity could paradoxically be protective for severe cytokine dysregulation, preventing the cytokine storm seen in severe COVID-19 cases. Appropriately powered and designed studies are still needed to draw conclusions on the effect of COVID-19.
In our own retrospective analysis of 33 confirmed SARS-CoV-2 infections between March 11 and April 17 in 12 participating German HIV centers, no excess morbidity or mortality was revealed (Haerter 2020). However, a multi-center cohort study which evaluated risk factors for morbidity and mortality of COVID‐19 in PLWH infected with SARS‐CoV‐2 in three countries, patients with severe COVID‐19 had a lower current CD4 T cell count and a lower CD4 T cell nadir, compared with patients with mild‐to‐moderate COVID‐19 (Hoffmann 2020). In a multivariate analysis, the only factor associated with risk for severe COVID‐19 was a current CD4+ T cell count of < 350/µl (adjusted odds ratio 2,85, 95% CI: 1,26‐6,44, p = 0,01). The only factor associ-ated with mortality was a low CD4 T cell nadir. In a large population study from South Africa, HIV was independently associated with increased COVID-19 mortality, showing an adjusted hazard ratio for mortality of 2,14 for HIV (95% CI: 1,70-2,70) (Boulle 2020). Among 286 HIV-infected patients who were included by US healthcare providers, mortality rates were higher in patients with low CD4 counts (< 200 cells/mm³) (Dandachi 2020). In a large study from the UK (Bhaskaran 2020), PLWH had higher risk of COVID-19 death than those without HIV after adjusting for age and sex: hazard ratio (HR) 2,90 (95% CI: 1,96–4,30; p < 0,0001).
There is still an ongoing debate about potential effects of antiretroviral therapies against SARS-CoV-2. For lopinavir/r (and darunavir/r), there is now strong evidence that they don’t work (see Treatment chapter, page 345). An ART regimen should not be changed to include a PI to prevent or treat COVID-19 (EACS 2020, US 2020). Tenofovir alafenamide (TAF) has some chemical similarities to remdesivir and has been shown to bind to SARS-CoV-2 RNA polymerase (RdRp) with high binding energies, and has been suggested as a potential treatment for COVID-19 (Elfiky 2020). In Spain, a large randomized Phase III placebo-controlled study (EPICOS, NCT04334928) compares the use of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), hydroxychloroquine or the combination of both versus placebo as prophylaxis for COVID-19 in healthcare workers. In combined cohorts from Milan, Madrid and Germany, there was no evidence that any specific antiretroviral drug (such as tenofovir or PIs) affected COVID-19 susceptibility or severity (Hoffmann 2020). Most patients, however, received TAF and not TDF for which preliminary data from Spain suggest a beneficial effect. Of 77.590 HIV+ persons receiving ART in Spain, 236 were diagnosed with COVID-19, 151 were hospitalized, 15 were admitted to the ICU, and 20 died (Del Amo 2020). The risk for COVID-19 hospitalization was higher among patients receiving TAF/FTC and ABC/3TC, compared to those receiving TDF/FTC. However, residual confounding by co-morbid conditions cannot be completely excluded. In a small group from France, attack rates were not lower with TDF/FTC in PrEP users (Charre 2020).
The most serious concern regarding HIV, however, is the collateral damage induced by COVID-19. In Western countries, there exist few reports of HIV+ patients having problems in gaining access to their HIV medications or having trouble taking them due to COVID-19 or the plans to manage it (Sanchez 2020). In contrast, disruption to delivery of health care in sub-Saharan African settings could well lead to adverse consequences beyond those from COVID-19 itself. Lockdown, transport restrictions and fear of coronavirus infection have already led to a dramatic drop in HIV and TB patients collecting medication in several African countries (Adepoju 2020). Using five different existing mathematical models of HIV epidemiology and intervention programs in sub-Saharan Africa, investigations have already estimated the impact of different disruptions to HIV prevention and treatment services. Predicted average relative excess in HIV-related deaths and new HIV infections (caused by unsuppressed HIV RNA during treatment interruptions) per year over 2020-2024 in countries in sub-Saharan Africa that would result from 3 months of disruption of HIV-specific services, were 1,20-1,27 for death and 1,02-1,33 for new infections, respectively. A 6-month interruption of ART would result in over 500.000 excess HIV deaths in sub-Saharan Africa (range of estimates 471.000 – 673.000). Disrupted services could also reverse gains made in preventing mother-to-child transmission. According to WHO, there is a clear need for urgent efforts to ensure HIV service continuity and preventing treatment interruptions due to COVID-19 restrictions in sub-Saharan Africa.
Bhaskaran K, Rentsch CT, MacKenna B, et al. HIV infection and COVID-19 death: a population-based cohort analysis of UK primary care data and linked national death registrations within the OpenSAFELY platform. Lancet HIV 2020, published 11 December. Full-text: https://doi.org/10.1016/S2352-3018(20)30305-2
Boulle A, Davies MA, Hussey H, et al. Risk factors for COVID-19 death in a population cohort study from the Western Cape Province, South Africa. Clin Infect Dis. 2020 Aug 29:ciaa1198. PubMed: https://pubmed.gov/32860699. Full-text: https://doi.org/10.1093/cid/ciaa1198
Charre C, Icard V, Pradat P, et al. Coronavirus disease 2019 attack rate in HIV-infected patients and in preexposure prophylaxis users. AIDS. 2020 Oct 1;34(12):1765-1770. PubMed: https://pubmed.gov/32889852. Full-text: https://doi.org/10.1097/QAD.0000000000002639
Dandachi D, Geiger G, Montgomery MW, et al. Characteristics, Co-morbidities, and Outcomes in a Multicenter Registry of Patients with HIV and Coronavirus Disease-19. Clin Infect Dis. 2020 Sep 9:ciaa1339. PubMed: https://pubmed.gov/32905581. Full-text: https://doi.org/10.1093/cid/ciaa1339
Del Amo J, Polo R, Moreno S, et al. Incidence and Severity of COVID-19 in HIV-Positive Persons Receiving Antiretroviral Therapy : A Cohort Study. Ann Intern Med. 2020 Oct 6;173(7):536-541. PubMed: https://pubmed.gov/32589451. Full-text: https://doi.org/10.7326/M20-3689
EACS & BHIVA. Statement on risk of COVID-19 for people living with HIV (PLWH). https://www.eacsociety.org/home/covid-19-and-hiv.html
Elfiky AA. Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study. Life Sci. 2020 Mar 25;253:117592. PubMed: https://pubmed.gov/32222463. Full-text: https://doi.org/10.1016/j.lfs.2020.117592
Härter G, Spinner CD, Roider J, et al. COVID-19 in people living with human immunodeficiency virus: a case series of 33 patients. Infection. 2020 Oct;48(5):681-686. PubMed: https://pubmed.gov/32394344. Full-text: https://doi.org/10.1007/s15010-020-01438-z
Hoffmann C, Casado JL, Härter G, et al. Immune deficiency is a risk factor for severe COVID-19 in people living with HIV. HIV Med. 2020 Dec 27. PubMed: https://pubmed.gov/33368966. Full-text: https://doi.org/10.1111/hiv.13037
Inciarte A, Gonzalez-Cordon A, Rojas J, et al. Clinical characteristics, risk factors, and incidence of symptomatic COVID-19 in adults living with HIV: a single-center, prospective observational study. AIDS. 2020 Aug 7. PubMed: https://pubmed.gov/32773471. Full-text: https://doi.org/10.1097/QAD.0000000000002643
Jewell BL, Mudimu E, Stover J, et al. Potential effects of disruption to HIV programmes in sub-Saharan Africa caused by COVID-19: results from multiple mathematical models. Lancet HIV. 2020 Sep;7(9):e629-e640. PubMed: https://pubmed.gov/32771089. Full-text: https://doi.org/10.1016/S2352-3018(20)30211-3
Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Co-morbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. 2020 Apr 22:e206775. PubMed: https://pubmed.gov/32320003. Full-text: https://doi.org/10.1001/jama.2020.6775
Sanchez TH, Zlotorzynska M, Rai M, Baral SD. Characterizing the Impact of COVID-19 on Men Who Have Sex with Men Across the United States in April, 2020. AIDS Behav. 2020 Apr 29:1-9. PubMed: https://pubmed.gov/32350773. Full-text: https://doi.org/10.1007/s10461-020-02894-2
U.S. Department of Health and Human Services. Interim Guidance for COVID-19 and Persons with HIV. https://aidsinfo.nih.gov/guidelines/html/8/covid-19-and-persons-with-hiv–interim-guidance-/554/interim-guidance-for-covid-19-and-persons-with-hiv
Immunosuppression may bear a higher risk for SARS-CoV-2 infection and severe COVID-19. But the story is not that simple. Neither is it clear what immunosuppression actually means, nor are the available data sufficient to draw any conclusion. We just don’t know enough. Nevertheless, some authors are trumpeting the news that there is an increased risk. A bad example? A systematic review and meta-analysis on 8 studies and 4007 patients came to the conclusion that “immunosuppression and immunodeficiency were associated with increased risk of severe COVID-19 disease, although the statistical differences were not significant” (Gao 2020). The authors also state that “in response to the COVID-19 pandemic, special preventive and protective measures should be provided.” There is null evidence for this impressive statement. The total number of patients with immunosuppression in the study was 39 (without HIV: 11!), with 6/8 studies describing less than 4 patients with different modalities of immunosuppression.
Despite the large absence of data, numerous viewpoints and guidelines have been published on how to manage immunosuppressed patients that may be more susceptible to acquire COVID-19 infection and develop severe courses. There are recommendations for intranasal corticosteroids in allergic rhinitis (Bousquet 2020), immunosuppressants for psoriasis and other cutaneous diseases (Conforti 2020, Torres 2020), rheumatic diseases (Favalli 2020, Figueroa-Parra 2020) or inflammatory bowel diseases (Kennedy 2020, Pasha 2020). The bottom line of these heroic attempts to balance the risk of immune-modifying drugs with the risk associated with active disease: what is generally needed, has to be done (or to be continued). Exposure prophylaxis is important.
However, several studies have indeed found evidence for deleterious effects of glucocorticoids, indicating that these drugs should be given with particular caution these days.
- In 600 COVID-19 patients with rheumatic diseases from 40 countries, multivariate-adjusted models revealed a prednisone dose ≥ 10 mg/day to be associated with higher odds of hospitalization. There was no risk with conventional disease-modifying anti-rheumatic drugs (DMARD) alone or in combination with biologics and Janus kinase (JAK) inhibitors (https://doi.org/10.1136/annrheumdis-2020-217871).
- In 525 patients with inflammatory bowel disease (IBD) from 33 countries (Brenner 2020), risk factors for severe COVID-19 included systemic corticosteroids (adjusted odds ratio 6,9, 95% CI: 2,3-20,5), and sulfasalazine or 5-aminosalicylate use (aOR 3,1). TNF antagonist treatment was not associated with severe COVID-19.
- In 86 patients with IBD and symptomatic COVID-19, among them 62 receiving biologics or JAK inhibitors, hospitalization rates were higher in patients treated with oral glucocorticoids, hydroxychloroquine and methotrexate but not with JAK inhibitors (Haberman 2020).
- In a large French database, including patients with inflammatory rheumatic and musculoskeletal diseases (iRMD), of 694 adults, 438 (63%) developed mild (not hospitalized), 169 (24%) moderate (hospitalized non-ICU) and 87 (13%) severe (ICU/deceased) disease. In multivariable imputed analyses, the variables associated with severe infection were age, male gender, hypertension and higher BMI. Use of corticosteroids (OR = 1,97), mycophenolate mofetil (OR = 6,6) and rituximab (OR = 4,21) were also risk factors.
Bousquet J, Akdis C, Jutel M, et al. Intranasal corticosteroids in allergic rhinitis in COVID-19 infected patients: An ARIA-EAACI statement. Allergy. 2020 Mar 31. PubMed: https://pubmed.gov/32233040. Full-text: https://doi.org/10.1111/all.14302
Brenner EJ, Ungaro RC, Gearry RB, et al. Corticosteroids, But Not TNF Antagonists, Are Associated With Adverse COVID-19 Outcomes in Patients With Inflammatory Bowel Diseases: Results From an International Registry. Gastroenterology. 2020 Aug;159(2):481-491.e3. PubMed: https://pubmed.gov/32425234. Full-text: https://doi.org/10.1053/j.gastro.2020.05.032
Conforti C, Giuffrida R, Dianzani C, Di Meo N, Zalaudek I. COVID-19 and psoriasis: Is it time to limit treatment with immunosuppressants? A call for action. Dermatol Ther. 2020 Jul;33(4):e13298. PubMed: https://pubmed.gov/32157783. Full-text: https://doi.org/10.1111/dth.13298
FAI2R / SFR / SNFMI / SOFREMIP / CRI / IMIDIATE consortium and contributors. Severity of COVID-19 and survival in patients with rheumatic and in-flammatory diseases: data from the French RMD COVID-19 cohort of 694 patients. Ann Rheum Dis. 2020 Dec 2:annrheumdis-2020-218310. PubMed: https://pubmed.gov/33268442. Full-text: https://doi.org/10.1136/annrheumdis-2020-218310
Favalli EG, Ingegnoli F, De Lucia O, Cincinelli G, Cimaz R, Caporali R. COVID-19 infection and rheumatoid arthritis: Faraway, so close! Autoimmun Rev. 2020 Mar 20:102523. PubMed: https://pubmed.gov/32205186. Fulltext: https://doi.org/10.1016/j.autrev.2020.102523
Figueroa-Parra G, Aguirre-Garcia GM, Gamboa-Alonso CM, Camacho-Ortiz A, Galarza-Delgado DA. Are my patients with rheumatic diseases at higher risk of COVID-19? Ann Rheum Dis. 2020 Mar 22. PubMed: https://pubmed.gov/32205336. Fulltext: https://doi.org/10.1136/annrheumdis-2020-217322
Gao Y, Chen Y, Liu M, Shi S, Tian J. Impacts of immunosuppression and immunodeficiency on COVID-19: a systematic review and meta-analysis. J Infect. 2020 May 14:S0163-4453(20)30294-2. PubMed: https://pubmed.gov/32417309. Full-text: https://doi.org/10.1016/j.jinf.2020.05.017
Gianfrancesco M, Hyrich KL, Al-Adely S, et al. Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann Rheum Dis. 2020 May 29. PubMed: https://pubmed.gov/32471903. Full-text: https://doi.org/10.1136/annrheumdis-2020-217871
Haberman R, Axelrad J, Chen A, et al. Covid-19 in Immune-Mediated Inflammatory Diseases – Case Series from New York. N Engl J Med. 2020 Apr 29. PubMed: https://pubmed.gov/32348641. Full-text: https://doi.org/10.1056/NEJMc2009567
Kennedy NA, Jones GR, Lamb CA, et al. British Society of Gastroenterology guidance for management of inflammatory bowel disease during the COVID-19 pandemic. Gut. 2020 Apr 17. PubMed: https://pubmed.gov/32303607. Full-text: https://doi.org/10.1136/gutjnl-2020-321244
Pasha SB, Fatima H, Ghouri YA. Management of Inflammatory Bowel Diseases in the Wake of COVID-19 Pandemic. J Gastroenterol Hepatol. 2020 Apr 4. PubMed: https://pubmed.gov/32246874. Full-text: https://doi.org/10.1111/jgh.15056
Torres T, Puig L. Managing Cutaneous Immune-Mediated Diseases During the COVID-19 Pandemic. Am J Clin Dermatol. 2020 Apr 10. pii: 10.1007/s40257-020-00514-2. PubMed: https://pubmed.gov/32277351. Full-text: https://doi.org/10.1007/s40257-020-00514-2.
Providing continuous and safe care for cancer patients is challenging in this pandemic. Oncologic patients may be vulnerable to infection because of their underlying illness and often immunosuppressed status and may be at increased risk of developing severe complications from the virus. On the other hand, the COVID-19 triage and management may stretch an already fragile system and potentially leave uncovered some vital activities, such as treatment administration or surgeries. It is well established that suboptimal timing and delayed oncologic treatment may lead to disease progression, leading to worse survival outcomes. There are several recommendations to minimizing exposure of oncology patients to COVID-19 without compromising oncological outcome: radiation for breast cancer (Coles 2020), hematopoietic cell transplant (Dholaria 2020) and leukemia treatment (Zeidan 2020).
- Compared to 519 statistically matched patients without cancer, 232 patients from Wuhan were more likely to have severe COVID-19 (64% vs 32%). An advanced tumour stage was a risk factor (odds ratio 2,60, 95% CI: 1,05–6,43) (Tian 2020).
- A systematic review of all studies until June 3 indicated that patients with hematological malignancies, especially those diagnosed recently (and likely those with myeloid malignancies), were at increased risk of death with COVID‐19 compared to the general population. The evidence that this risk is higher than for those with solid malignancies was conflicting (El-Sharkawi 2020).
- Patients with Chronic Lymphatic Leukemia (CLL) seem to be at particular high risk of death. Of 198 CLL patients diagnosed with symptomatic COVID-19, 39% were treatment-naïve (“watch and wait”) while 61% received at least one CLL therapy. At 16 days, the overall CFR was 33%, while another 25% were still in hospital (Mato 2020).
- In a retrospective study from Italy, including 536 patients with a diagnosis of a hematological malignancy, 198 (37%) had died. Progressive disease status, diagnosis of acute myeloid leukemia, indolent or aggressive NHL were associated with worse overall survival (Passamonti 2020).
- In a large cohort study of 928 cancer patients with COVID-19 from the USA, Canada, and Spain, most prevalent malignancies were breast (21%) and prostate (16%). In total 121 (13%) patients had died. Independent risk factors were an ECOG status of 2 or higher and “active” cancer (Kuderer 2020).
- SARS-CoV-2 viral load in nasopharyngeal swab specimens of 100 patients with cancer who were admitted to three New York City hospitals predicted outcome. The authors also found that patients with hematologic malignancies had higher median viral loads than patients without cancer (Westblade 2020).
Does anti‐neoplastic treatment lead to increased risk of complications?
- Among a total of 309 patients, cytotoxic chemotherapy administered within 35 days of a COVID-19 diagnosis was not significantly associated with a severe or critical COVID-19 event. However, patients with active hematologic or lung malignancies, lymphopenia, or baseline neutropenia had worse COVID-19 outcomes.
- Among 423 cases of symptomatic COVID-19 patients, 40% were hospitalized and 12% died within 30 days. Age older than 65 years and treatment with immune checkpoint inhibitors were predictors for hospitalization and severe disease, whereas receipt of chemotherapy and major surgery were not (Robilotti 2020).
- In a systemic review and meta-analysis of 34 adult and 5 pediatric studies (3377 patients) from Asia, Europe, and North America (14 of 34 adult studies included only hospitalized patients), adult patients with hematologic malignancy and COVID-19 found a 34% risk of death (Vijenthira 2020), whereas pediatric patients had a 4% risk of death. Patients on systemic anticancer therapy had a similar risk of death to patients on no treatment.
- Among 77 patients with SARS-CoV-2 who were recipients of cellular therapy (Allo, 35; Auto, 37; CAR T, 5; median time from cellular therapy, 782 days), overall survival at 30 days was 78% (Shah 2020). Mortality was largely driven by patients with active malignancy, especially relapsed leukemia, in whom the goals of care were affected by COVID-19 severity. Many patients were able to recover from COVID-19 and mount an antibody response.
All these studies are not controlled. A myriad of potential factors may lead to a difference in COVID-19 outcomes and risk for patients with malignancies, compared to the rest of the population (nice review: El-Sharkawi 2020). These include patient behavior (exposure to the virus?), healthcare professional behavior (i.e., testing patients with a history of cancer for COVID‐19 more frequently?), biological differences but also several confounders (more co-morbidities, older age in cancer patients). Continued analysis of the data is required to attain further understanding of the risk factors for cancer patients in this pandemic.
Finally, it’s not only treatment, it’s also diagnosis. Diagnostic delays may lead to an increase in the numbers of avoidable cancers (Maringe 2020). During the pandemic, a large cross-sectional study in the US has observed significant declines in several cancer types, ranging from 24,7% for pancreatic cancer to 51,8% for breast cancer, indicating that a delay in diagnosis will likely lead to presentation at more advanced stages and poorer clinical outcomes (Kaufman 2020).
Coles CE, Aristei C, Bliss J, et al. International Guidelines on Radiation Therapy for Breast Cancer During the COVID-19 Pandemic. Clin Oncol (R Coll Radiol). 2020 May;32(5):279-281. PubMed: https://pubmed.gov/32241520. Full-text: https://doi.org/10.1016/j.clon.2020.03.006
Dholaria B, Savani BN. How do we plan hematopoietic cell transplant and cellular therapy with the looming COVID-19 threat? Br J Haematol. 2020 Apr;189(2):239-240. PubMed: https://pubmed.gov/32180224. Full-text: https://doi.org/10.1111/bjh.16597
El-Sharkawi D, Iyengar S. Haematological Cancers and the risk of severe COVID-19: Exploration and critical evaluation of the evidence to date. Br J Haematol. 2020 Jun 19. PubMed: https://pubmed.gov/32559308. Full-text: https://doi.org/10.1111/bjh.16956.
Jee J, Foote MB, Lumish M, et al. Chemotherapy and COVID-19 Outcomes in Patients With Cancer. J Clin Oncol. 2020 Oct 20;38(30):3538-3546. PubMed: https://pubmed.gov/32795225. Full-text: https://doi.org/10.1200/JCO.20.01307
Kaufman HW, Chen Z, Niles J, Fesko Y. Changes in the Number of US Patients With Newly Identified Cancer Before and During the Coronavirus Disease 2019 (COVID-19) Pandemic. JAMA Netw Open. 2020 Aug 3;3(8):e2017267. PubMed: https://pubmed.gov/32749465. Full-text: https://doi.org/10.1001/jamanetworkopen.2020.17267
Kuderer NM, Choueiri TK, Shah DP, et al. Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. Lancet. 2020 May 28:S0140-6736(20)31187-9. PubMed: https://pubmed.gov/32473681. Full-text: https://doi.org/10.1016/S0140-6736(20)31187-9
Maringe C, Spicer J, Morris M, et al. The impact of the COVID-19 pandemic on cancer deaths due to delays in diagnosis in England, UK: a national, population-based, modelling study. Lancet Oncol. 2020 Aug;21(8):1023-1034. PubMed: https://pubmed.gov/32702310. Full-text: https://doi.org/10.1016/S1470-2045(20)30388-0
Mato AR, Roeker LE, Lamanna N, et al. Outcomes of COVID-19 in Patients with CLL: A Multicenter, International Experience. Blood. 2020 Jul 20:blood.2020006965. PubMed: https://pubmed.gov/32688395. Full-text: https://doi.org/10.1182/blood.2020006965.
Passamonti F, Cattaneo C, Arcaini L, et al. Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study. Lancet Haematol. 2020 Oct;7(10):e737-e745. PubMed: https://pubmed.gov/32798473. Full-text: https://doi.org/10.1016/S2352-3026(20)30251-9
Robilotti EV, Babady NE, Mead PA, et al. Determinants of COVID-19 disease severity in patients with cancer. Nat Med. 2020 Aug;26(8):1218-1223. PubMed: https://pubmed.gov/32581323. Full-text: https://doi.org/10.1038/s41591-020-0979-0
Shah GL, DeWolf S, Lee YJ, et al. Favorable outcomes of COVID-19 in recipients of hematopoietic cell transplantation. J Clin Invest. 2020 Nov 16:141777. PubMed: https://pubmed.gov/32897885. Full-text: https://doi.org/10.1172/JCI141777
Tian J, Yuan X, Xiao J, et al. Clinical characteristics and risk factors associated with COVID-19 disease severity in patients with cancer in Wuhan, China: a multicentre, retrospective, cohort study. Lancet Oncol. 2020 May 29:S1470-2045(20)30309-0. PubMed: https://pubmed.gov/32479790. Full-text: https://doi.org/10.1016/S1470-2045(20)30309-0
Vijenthira A, Gong IY, Fox TA. Outcomes of patients with hematologic malig-nancies and COVID-19: a systematic review and meta-analysis of 3377 pa-tients. Blood December 17, 2020, 136 (25): 2881–2892. Full-text: https://doi.org/10.1182/blood.2020008824
Westblade LF, Brar G, Pinheiro LC, et al. SARS-CoV-2 Viral Load Predicts Mortality in Patients with and without Cancer Who Are Hospitalized with COVID-19. Cancer Cell. 2020 Nov 9;38(5):661-671.e2. PubMed: https://pubmed.gov/32997958. Full-text: https://doi.org/10.1016/j.ccell.2020.09.007
Zeidan AM, Boddu PC, Patnaik MM, et al. Special considerations in the management of adult patients with acute leukaemias and myeloid neoplasms in the COVID-19 era: recommendations from a panel of international experts. Lancet Haematol. 2020 Aug;7(8):e601-e612. PubMed: https://pubmed.gov/32563283. Full-text: https://doi.org/10.1016/S2352-3026(20)30205-2
During a health crisis such as the COVID pandemic, it is crucial to carefully balance cost and benefits in performing organ transplantation (Andrea 2020). There is no doubt that the current situation has deeply affected organ donation and that this represents an important collateral damage of the pandemic. All Eurotransplant countries have implemented preventive screenings policies for potential organ donors. For detailed information on the national policy, please visit https://www.eurotransplant.org/2020/04/07/covid-19-and-organ-donation/. Preliminary data indicate a significant reduction in transplantation rates even in regions where COVID-19 cases are low, suggesting a global and nationwide effect beyond the local COVID-19 infection prevalence (Loupy 2020). During March and April, the overall reduction in deceased donor transplantations since the COVID-19 outbreak was 91% in France and 51% in the USA, respectively. In both France and the USA, this reduction was mostly driven by kidney transplantation, but a substantial effect was also seen for heart, lung, and liver transplants, all of which provide meaningful improvement in survival probability. In Germany, however, compared with the previous year, the cumulative numbers of deceased organ donors and transplants showed no significant reduction (Qu 2020).
Solid organ transplant recipients are generally at higher risk for complications of respiratory viral infections (in particular influenza), due to their chronic immunosuppressive regimen, and this may hold particularly true for SARS-CoV-2 infection. The first cohort of COVID-19 in transplant recipients from the US indeed indicated that transplant recipients appear to have more severe outcomes (Pereira 2020). Some key studies:
Liver: In the largest cohort, 16/100 patients died from COVID-19. Of note, mortality was observed only in patients aged 60 years or older (16/73) and was more common in males than in females (Belli 2020). Although not statistically significant, more patients who were transplanted at least 2 years earlier died than did those who received their transplant within the past 2 years (18% vs 5%). A systematic search on June 15 revealed 223 liver transplant recipients with COVID-19 in 15 studies (Fraser 2020). The case fatality rate was 19,3%. Dyspnea on presentation, diabetes mellitus, and age 60 years or older were significantly associated with increased mortality (p = 0.01) with a trend to a higher mortality rate observed in those with hypertension and those receiving corticosteroids at the time of COVID-19 diagnosis. However, in a multicenter cohort study, comparing 151 adult liver transplant recipients from 18 countries with 627 patients who had not undergone liver transplantation, liver transplantation did not significantly increase the risk of death in patients with SARS-CoV-2 infection (Webb 2020).
Kidney: In a single center with 36 kidney transplant recipients, 10/36 died (Akalin 2020). Patients appear to have less fever as an initial symptom, lower CD4 and CD8 T cell counts and more rapid clinical progression.
Heart: In a case series of 28 patients who had received a heart transplant in a large academic center in New York, 22 patients (79%) were hospitalized. At the end of the follow-up, 4 remained hospitalized and 7 (25%) had died (Latif 2020). In Germany, mortality was also high, and 7/21 patients died (Rivinius 2020).
Andrea G, Daniele D, Barbara A, et al. Coronavirus Disease 2019 and Transplantation: a view from the inside. Am J Transplant. 2020 Mar 17. PubMed: https://pubmed.gov/32181969. Fulltext: https://doi.org/10.1111/ajt.15853
Belli LS, Duvoux C, Karam V, et al. COVID-19 in liver transplant recipients: preliminary data from the ELITA/ELTR registry. Lancet Gastroenterol Hepatol. 2020 Aug;5(8):724-725. PubMed: https://pubmed.gov/32505228. Full-text: https://doi.org/10.1016/S2468-1253(20)30183-7
Fraser J, Mousley J, Testro A, Smibert OC, Koshy AN. Clinical Presentation, Treatment, and Mortality Rate in Liver Transplant Recipients With Coronavirus Disease 2019: A Systematic Review and Quantitative Analysis. Transplant Proc. 2020 Jul 30:S0041-1345(20)32634-8. PubMed: https://pubmed.gov/32891405. Full-text: https://doi.org/10.1016/j.transproceed.2020.07.012
Latif F, Farr MA, Clerkin KJ, et al. Characteristics and Outcomes of Recipients of Heart Transplant With Coronavirus Disease 2019. JAMA Cardiol. 2020 May 13:e202159. PubMed: https://pubmed.gov/32402056. Full-text: https://doi.org/10.1001/jamacardio.2020.2159
Loupy A, Aubert O, Reese PP, Bastien O, Bayer F, Jacquelinet C. Organ procurement and transplantation during the COVID-19 pandemic. Lancet. 2020 May 23;395(10237):e95-e96. PubMed: https://pubmed.gov/32407668. Full-text: https://doi.org/10.1016/S0140-6736(20)31040-0
Pereira MR, Mohan S, Cohen DJ, et al. COVID-19 in Solid Organ Transplant Recipients: Initial Report from the US Epicenter. Am J Transplant. 2020 Apr 24. PubMed: https://pubmed.gov/32330343. Full-text: https://doi.org/10.1111/ajt.15941
Qu Z, Oedingen C, Bartling T, Schrem H, Krauth C. Organ procurement and transplantation in Germany during the COVID-19 pandemic. Lancet. 2020 Oct 31;396(10260):1395. PubMed: https://pubmed.gov/33129390. Full-text: https://doi.org/10.1016/S0140-6736(20)32213-3
Rivinius R, Kaya Z, Schramm R, et al. COVID-19 among heart transplant recipients in Germany: a multicenter survey. Clin Res Cardiol. 2020 Aug 11. PubMed: https://pubmed.gov/32783099. Full-text: https://doi.org/10.1007/s00392-020-01722-w
Webb GJ, Marjot T, Cook JA, et al. Outcomes following SARS-CoV-2 infection in liver transplant recipients: an international registry study. Lancet Gastroenterol Hepatol. 2020 Nov;5(11):1008-1016. PubMed: https://pubmed.gov/32866433. Full-text: https://doi.org/10.1016/S2468-1253(20)30271-5
The OpenSAFELY project analysed factors associated with COVID-19 deaths in 17 million patients. The picture that arose differs significantly from initial reports. For example, hypertension is not an independent risk factor for COVID-19 death, but renal disease very much is. Dialysis (aHR 3,69), organ transplantation (aHR 3,53) and CKD (aHR 2,52 for patients with eGFR < 30 mL/min/1.73 m2) represent three of the four co-morbidities associated with the highest mortality risk from COVID-19. The risk associated with CKD Stages 4 and 5 was higher than the risk associated with diabetes mellitus (aHR range 1,31–1,95, depending upon glycemic control) or chronic heart disease (aHR 1,17). These findings define essential action points, among which is advocating the inclusion of CKD patients in clinical trials when testing the efficacy of drugs and vaccines to prevent severe COVID-19 (ERA 2020).
Basile C, Combe C, Pizzarelli F, et al. Recommendations for the prevention, mitigation and containment of the emerging SARS-CoV-2 (COVID-19) pandemic in haemodialysis centres. Nephrol Dial Transplant. 2020 Mar 20. pii: 5810637. PubMed: https://pubmed.gov/32196116. Fulltext: https://doi.org/10.1093/ndt/gfaa069
ERA-EDTA Council, ERACODA Working Group. Chronic kidney disease is a key risk factor for severe COVID-19: a call to action by the ERA-EDTA. Nephrology Dialysis Transplantation December 19 2020. Full-text: https://academic.oup.com/ndt/advance-article/doi/10.1093/ndt/gfaa314/6041849
Ultimately, the current situation might lead to substantial changes in how research and medicine are practiced in the future. The SARS-CoV-2 pandemic has created major dilemmas in almost all areas of health care. Scheduled operations, numerous types of treatment and appointments have been cancelled world-wide or postponed to priorities hospital beds and care for those who are seriously ill with COVID-19. Throughout the world, health systems had to consider rapidly changing responses while relying on inadequate information. In some settings such as HIV or TB infection, oncology or solid organ transplantation, these collateral damages may have been even greater than the damage caused by COVID-19 itself. Treatment interruptions, disrupted drug supply chains and consequent shortages will likely exacerbate this issue. During the next months, we will learn more and provide more information on the consequences of this crisis on various diseases.
French JA, Brodie MJ, Caraballo R, et al. Keeping people with epilepsy safe during the Covid-19 pandemic. Neurology. 2020 Apr 23. PubMed: https://pubmed.gov/32327490. Full-text: https://doi.org/10.1212/WNL.0000000000009632
Li L, Li F, Fortunati F, Krystal JH. Association of a Prior Psychiatric Diagnosis With Mortality Among Hospitalized Patients With Coronavirus Disease 2019 (COVID-19) Infection. JAMA Netw Open. 2020 Sep 1;3(9):e2023282. PubMed: https://pubmed.gov/32997123. Full-text: https://doi.org/10.1001/jamanetworkopen.2020.23282
Louapre C, Collongues N, Stankoff B, et al. Clinical Characteristics and Outcomes in Patients With Coronavirus Disease 2019 and Multiple Sclerosis. JAMA Neurol. 2020 Sep 1;77(9):1079-1088. PubMed: https://pubmed.gov/32589189. Full-text: https://doi.org/10.1001/jamaneurol.2020.2581
Taquet M, Luciano S, Geddes JR, et al. Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62,354 COVID-19 cases in the USA. Lancet Psychiatry November 09, 2020. Full-text: https://doi.org/10.1016/S2215-0366(20)30462-4
Wang H, Li T, Barbarino P, et al. Dementia care during COVID-19. Lancet. 2020 Apr 11; 395(10231):1190-1191. PubMed: https://pubmed.gov/32240625. Full-text: https://doi.org/10.1016/S0140-6736(20)30755-8
Yao H, Chen JH, Xu YF. Patients with mental health disorders in the COVID-19 epidemic. Lancet Psychiatry. 2020 Apr;7(4):e21. PubMed: https://pubmed.gov/32199510. Full-text: https://doi.org/10.1016/S2215-0366(20)30090-0
Dave M, Seoudi N, Coulthard P. Urgent dental care for patients during the COVID-19 pandemic. Lancet. 2020 Apr 3. PubMed: https://pubmed.gov/32251619. Full-text: https://doi.org/10.1016/S0140-6736(20)30806-0
Doglietto F, Vezzoli M, Gheza F, et al. Factors Associated With Surgical Mortality and Complications Among Patients With and Without Coronavirus Disease 2019 (COVID-19) in Italy. JAMA Surg. 2020 Jun 12. PubMed: https://pubmed.gov/32530453. Full-text: https://doi.org/10.1001/jamasurg.2020.2713.
Ibáñez-Samaniego L, Bighelli F, Usón C, et al. Elevation of liver fibrosis index FIB-4 is associated with poor clinical outcomes in patients with COVID-19. J Infect Dis. 2020 Jun 21:jiaa355. PubMed: https://pubmed.gov/32563190. Full-text: https://doi.org/10.1093/infdis/jiaa355