key: cord-1037554-j0pmjxdg
authors: Alharbi, Mohammed Ghannam; Alanazi, Nouf; Yousef, Aroob; Alanazi, Nora; Alotaibi, Bader; Aljurf, Mahmoud; El Fakih, Riad
title: COVID-19 associated with immune thrombocytopenia: a systematic review and meta-analysis
date: 2022-02-12
journal: Expert review of hematology
DOI: 10.1080/17474086.2022.2029699
sha: a7a9f5359182c2ca76014195dab9c1c2ce3b7fd3
doc_id: 1037554
cord_uid: j0pmjxdg

BACKGROUND: Immune thrombocytopenia, also known as immune thrombocytopenic purpura (ITP), has emerged as a significant COVID-19-associated complication. This study analyzes the published literature of case reports and case series regarding COVID-19 infection associated with ITP. METHODOLOGY: In this systematic review and meta-analysis, a systematic search was conducted through PubMed, Web of Science, and Medline through Clarivate and EBSCO to include the eligible studies. The authors utilized Review Manager 5.4 to conduct quantitative data synthesis for the condition of interest analysis. RESULTS: A total of 13 eligible case reports and case series with 42 patients were included in this study; 54.8% of them were male. The pooled mean age of all participants was (59.5 ± 19) years with a median age of 63 years. The estimated mean time from diagnosis with COVID-19 to ITP development was 18.1 ± 21 days and the mean time to recovery from ITP was 5.8 ± 4.8 days. The pooled random effect of mean platelet count in the included six studies was 14.52, CI [8.79, 20.25]. CONCLUSION: Our analysis shows that ITP secondary to COVID-19 infection is slightly more prevalent among males (54.8%). Elderly patients were more vulnerable to the disease. Most cases developed ITP within 2–3 weeks after COVID-19 infection and recovered in less than one week from ITP.

By the end of 2019, a series of lower respiratory tract infection cases of unknown cause emerged in Wuhan, China [1] . A few weeks later, deep sequencing of lower respiratory tract samples identified a novel virus as the culprit, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the disease was named 'coronavirus infectious disease . The infection relentlessly spread throughout the world and was designated a pandemic by the World Health Organization (WHO) in March 2020 [2] .

Coronaviruses, initially characterized in 1966, are enclosed single-stranded large RNA viruses that infect humans and a variety of animals [3] . As of July 2021, the COVID-19 pandemic has affected 223 countries, with more than 185 million confirmed cases and more than 4 million confirmed deaths worldwide [4] .

Acute respiratory distress syndrome (ARDS), cardiac problems, and thromboembolic complications are the major causes of COVID-19-related deaths. Hyperinflammatory states resembling hemophagocytic lymphohistiocytosis (HLH) and coagulopathy resembling the hypercoagulable stage of disseminated intravascular coagulation (DIC) have been reported with this infection [5] .

Thrombocytopenia was seen during the severe acute respiratory syndrome (SARS) caused by another coronavirus in 2002-2003, and its presence was linked to the severity of the infection [6, 7] . Thrombocytopenia is a well-known complication of many viral infections, with many underlying mechanisms causing the drop in platelet count. Immune-mediated thrombocytopenia is one of these mechanisms (ITP) [8] . With the current SARS-CoV-2 pandemic, thrombocytopenia was reported in up to 36% of patients 9. [9] [10] [11] The proposed mechanisms of hematopoietic dysfunction with the SARS-CoV-2 infection are many, including but not limited to changes in megakaryocytic differentiation and maturation resulting from infection of hematopoietic stem cells and megakaryocytes, changes in the bone marrow microenvironment caused by inflammation, a decline in TPO production by liver cells and by the lung damage caused by SARS-CoV-2 infection that may alter megakaryocyte fragmentation, and platelet production in pulmonary vessels [12] .

ITP is characterized by a platelet count of < 100 × 10 9 /L and often manifests as petechial or purpuric rashes [13] . ITP has been reported following many viral infections, including but not limited to hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), cytomegalovirus (CMV), varicellazoster virus (VZV), and zika viruses [14] . Thrombocytopenia can result from other factors including some commonly associated with COVID-19 infections as the high incidence of hypercoagulability, thrombosis, and eventually DIC [12] .

In this systematic review and meta-analysis, we aimed to collect and analyze the published case reports and case series of COVID-19 infections associated with ITP.

An electronic systematic literature search of three major databases, PubMed, Web of Science and Medline through Clarivate, and EBSCO, was conducted to include relevant and eligible study articles. The search was limited to the English language. The relevant literature was searched using the following keywords, which corresponded to Mesh terms in PubMed or subject terms in EBSCO; 'COVID-19,' 'severe acute respiratory syndrome coronavirus-2,' 'SARS-CoV-2,' 'immune thrombocytopenia,' 'immune thrombocytopenic purpura,' 'immune cytopenia,' 'petechiae,' 'bleeding,' and 'hemorrhage.' Boolean operators such as 'OR' and 'AND' were used in combination with the appropriate keywords. The search results included full texts, openly available publications, human trials, and the English language.

Inclusion criteria:

• Case reports and case series that investigate the association between COVID-19 infection and ITP. • The condition will be considered ITP as reported in the literature, after excluding other possible causes or types of thrombocytopenia. • No age or sex restrictions were set.

Exclusion criteria:

• Studies not conducted in the English language. • Studies reporting other types or causes of thrombocytopenia than ITP.

Rayyan (QCRI) [15] was used to identify the duplicate records of the search strategy results. The reviewers screened titles and abstracts for convenience by investigating the pooled search results utilizing a set of inclusion/ exclusion criteria. The researchers evaluated the full text of the study articles that met the inclusion criteria. They overcame any disagreements or conflicts through debate and discussion. To comprise the eligible articles, a data extraction sheet was created. The reviewers extracted data of the study titles, authors, study year, study design, study population, participants' age, and gender, the case presentation, medical history, diagnosis, and the laboratory investigations of the selected cases.

To produce a qualitative overview of the included research characteristics and result data, summary tables containing the collected details from the eligible studies were presented. After the data processing was evaluated, the extent of the proposed pooled analyses was investigated. Following the conclusion of data extraction in this meta-analysis, decisions were made on how to improve the use of case and control data and the numerical data of the included case reports. A qualitative synthesis of the determined data was performed regardless of the feasibility of the pooled meta-analyses. Studies that fulfilled the full-text inclusion criteria but did not present numerical data on ITP among COVID-19 patients were excluded. To conduct quantitative data synthesis for the condition of interest analysis, the authors utilized Review Manager 5.4 [16] . A random-effects meta-analysis was used to investigate the association between COVID-19 infection and ITP. An I-square statistic was used to measure heterogeneity as part of the pooled meta-analysis. To evaluate publication bias, the funnel plot and funnel plot symmetry measures were obtained.

The initial systematic search came out with a total of 466 studies. Rayyan (QCRI) identified and removed 84 duplicates from these studies. After the title and abstract screening, 224 studies were removed because of irrelevant findings and inappropriate research type or design, followed by the full-text screening and removal of an additional 145 studies due to irrelevant analysis or wrong outcome. This analysis eventually resulted in a total of 13 eligible case reports and case series. The selection process and identification are shown in Figure 1 

The included case reports and series comprised a total of 42 participants; 23 (54.8%) of them were male. The pooled mean age of all participants was (59.5 ± 19) years with a median age of 63 years.

This study included a total of 7 case reports, two of them were reported from the United States [17, 18] , one from Canada [19] , one from Italy [20] , one from Turkey [21] , and one from Greece [22] . The lowest platelet count ranged from 1 × 10 9 /L in Clerici et al. [20] to 23 × 10 9 /L in Lévesque et al. [19] . These characteristics are presented in Table 1 .

Lévesque et al. reported a 53-year-old male patient who presented with a three-day history of dyspnea, dry cough, fever, and a preexisting medical history of hypertension, dyslipidemia, type 2 diabetes (T2DM), and a body mass index (BMI) of 24. The patient recovered after being diagnosed with ITP that manifested late after the COVID-related classic clinical symptoms started. He had no cutaneous manifestations of ITP nor severe hemorrhage [19] .

Bennett et al. reported a case of a 73-year-old female patient who presented with fever, shortness of breath, and diarrhea and a preexisting medical history of hypertension and hyperlipidemia. The patient suffered from a sharp decrease in the platelet count without response on transfusion of platelet units, so ITP was suspected. The patient recovered after being diagnosed with COVID-19 infection-associated ITP [17] .

Clerici et al. reported a 64-year-old male patient presenting with unexplained fever following contact with a known SARS-CoV-2 positive subject, and traumatic epistaxis and mucocutaneous petechiae were reported. The patient recovered after being diagnosed with COVID-19 infection and ITP [20] .

Martincic et al. reported a 48-year-old male patient who presented with dyspnea, cough, fever, headache, and muscle ache and a preexisting medical history of T2DM, obesity, and obstructive sleep apnea. Later, on the 9 th day after admission, the patient had non-traumatic macroscopic hematuria, minor bleeding in the oral mucosa, and blood clots in the gastric residual volume, and complete blood count indicated the incidence of thrombocytopenia. The patient recovered after being diagnosed with COVID-19 associated with ITP [23] .

Hindilerden et al. reported a case of an 86-year-old male patient who presented with a one-week history of excessive bruising, fatigue, fever, and dry cough and a preexisting medical history of hypertension and T2DM. After being diagnosed with ITP associated with COVID-19 with purpuric eruptions all over the skin and hemorrhagic bullae in the oral cavity, the patient recovered well [21] .

Metallidis et al. reported a 33-year-old female patient who presented with a two-day history of mild muscle ache, pharyngula, low-grade fever, and a preexisting medical history of diabetes mellitus type 1 (T1DM). Platelet count markedly dropped on the 6 th day of admission, so ITP was suspected. The patient recovered after being diagnosed with COVID-19 induced immune thrombocytopenia [22] .

Ayesh et al. reported a case of a 76-year-old female patient who presented with a 5-day history of skin rash, fatigue, mouth pain, visual disturbances, and arthralgia and a preexisting medical history of insulin-dependent T2DM essential hypertension, cerebrovascular accident, and hyperlipidemia. The patient recovered after being diagnosed with secondary ITP associated with COVID-19 [18] .

A total of 6 case series with 35 patients were included in this study. One study was conducted in Turkey [24] , one in Greece [25] , one in the Netherlands [26] , one in the USA [27] , and one in France [28] . The participants' ages ranged from a 3-year-old female patient who presented with a low-grade fever for one day, epistaxis, and melena and was diagnosed with ITP [25] to an 89-year-old male patient who presented with fever, cough, shortness of breath (SOB), and gastrointestinal (GI) symptoms and a preexisting medical history of hypertension, atrial fibrillation, DM, and chronic kidney disease (CKD) [27] . All of the 35 included patients were diagnosed with COVID-19 associated ITP. Their characteristics are presented in Table 2 . Table 3 presents the clinical characteristics of the included case reports and case series. The majority of cases were treated with intravenous immunoglobulin (IVIG) and intravenous dexamethasone, with good response and complete resolution of ITP. Most patients who received platelet transfusion alone did not improve. Two patients received romiplostim in combination with IVIG and showed complete response [19, 20] . Methylprednisolone only [25] , or in combination with IVIG [19, 26, 27] , Romiplostim [20] , and eltrombopag [27] lead to complete response. Response to the administered treatment and then relapse occurred in the following cases; a patient who received dexamethasone 40 mg (D1-D4), IVIG (D1-D2), eltrombopag (D5-D28) [26] , prednisone, dexamethasone, and prednisone with IVIG [27] . The estimated mean time from diagnosis with COVID-19 to ITP development was (18.1 ± 21) days and ranged from diagnosing ITP at the same time of diagnosis of COVID-19 infection to 125 days. The estimated mean time to recovery from ITP was (5.8 ± 4.8) days and ranged from 2 to 22 days.

The forest plot through random effect analysis shows that the mean platelet count in the included six studies was 14.52, CI [8.79, 20.25 ] with significant (P < 0.000) overall effect analysis. There was significant heterogeneity among the studies (I 2 = 97%, P < 0.000) ( Figure 2 ). Visual inspection of the funnel plot reveals publication bias due to some asymmetry ( Figure 3 ).

Immune thrombocytopenia is typically diagnosed retrospectively after eliminating other potential causes of thrombocytopenia and after assessing the response to therapy [30] . A spectrum of severity characterizes the COVID-19 infection, ranging from asymptomatic to critical [31] . The diagnosis of COVID-19-associated ITP is challenging because of many confounding variables in these patients. This systematic review and meta-analysis summarized the published relevant literature of case reports and case series about COVID-19 infection associated with ITP. This study found that the incidence of ITP secondary to COVID-19 infection is slightly more common among males (54.8%) than females; moreover, it was more prevalent among the elderly with mean age of (59.5 ± 19) years and a median age of 63 years. A similar systematic review conducted by Bhattacharjee et al. has also reported that most ITP cases (71%) were found to be elderly with a median age > 60 years [15] .

Two cases were diagnosed with ITP at the same time as COVID-19 diagnosis and many other cases within the first week; this may be attributable to patients' failure to report the development of the initial COVID-19 symptom. Regarding management of ITP in COVID-19 patients, observation alone is advised in such conditions; nevertheless, treatment with glucocorticoids might be considered for people with comorbidities, age > 60 years, or on anticoagulation according to contemporary therapy guidelines. Most cases in this study were treated with IVIG in different doses (400 mg/kg/day for 5 days or 1 g/kg for 1-3 days) and dexamethasone. This could be due to concerns about the use of glucocorticoids in COVID-19 patients with the severe acute respiratory disease [5] . Nonetheless, IVIG is recommended for individuals at risk of serious bleeding since it can cause a platelet count increase in 12-48 h, whereas glucocorticoids generally result in a 2-5 day improvement in platelet count [32] . According to the American Society of Hematology, dexamethasone (40 mg/ day for 4 days) or prednisolone (1 mg/kg/day) with tapering (depending on response and for a maximum length of 6 weeks) is recommended. Dexamethasone may be favored over prednisolone in studies on people with ITP due to a higher response rate at 7 days [30] . Relapse and lack of sustained response in monotherapy of IVIG were also reported [26] . It is hypothesized that this relative resistance to IVIG therapy was caused by high antibody load owing to underlying severe COVID-19 and enhanced platelet consumption or loss of IVIG due to active bleeding [19] . Thrombopoietin receptor agonists (TP-RA), which can cause a sustained increase in platelet count 1-2 weeks after treatment, can also assist in avoiding severe thrombocytopenia recurrences [32] . Because of the increased risk of thrombotic events and hepatotoxicity, recommendations suggest using TP-RA only as a second-line treatment in COVID-19 patients with no evidence of severe disseminated intravascular coagulation (DIC) [33] .

To offer a clear viewpoint indicating the predictive significance of platelet count in this new infection, we presented a pooled mean platelet count in 6 included studies (14.52, CI [8.79, 20.25] ) which implies that COVID-19 patients are more likely to develop thrombocytopenia. This was also consistent with Bashash et al., who reported that low platelet count was found to be related to an increased risk of severe COVID-19 illness, with a pooled mean difference of (−21.5, 95% CI [−31.57, −11.43]).

Mean time (±SD) of recovery from ITP was 5.8 ± 4.8 days. This is similar to the findings of a retrospective study that included 3255 patients that found that the median time of recovery was 4 days [27] .

Our main limitations are the low number of included cases, the heterogeneity of data reported, the absence of a confirmatory test to confirm SARS-CoV-2-associated ITP, the absence of a standard definition for SARS-CoV-2-associated ITP, the absence of information regarding time points (time from COVID-19 to ITP, duration of thrombocytopenia, etc.), and treatment response. Additionally, there is an inherent 20 days 14 days On ITP days 1 and 2, they provided 1 g of IVIG per kilogram of body weight daily, and on days 3-6, they administered 40 mg of intravenous dexamethasone daily. They also gave him a platelet, and they subsequently chose to use second-line treatments, giving romiplostim daily from ITP days 5-14 and vincristine on ITP day 9. From ITP days 10-13, they additionally gave 500 mg of intravenous methylprednisolone in pulses. Bennett et al., 2020 [17] NA 5 days The patient received one unit of platelets, but his platelet count did not improve. ITP was suspected; therefore, IVIG was given at 1 g/kg/day for two doses. She came to the hematology clinic 28 days following discharge with a platelet count of 8 K/L. Clerici et al., 2020 [20] NA 10 days following the initial dosage of romiplostim

The patient had a platelet pool transfusion with no significant change in platelet count after 45 minutes, as well as methylprednisolone 1 mg/kg. Because the platelet count remained extremely low, IVIG (400 mg/kg/day for 5 days) was administered. Rituximab was avoided, and romiplostim at a dose of 1 g/kg was used instead. One week and ten days following the initial dosage of romiplostim, the platelet count has developed. Martincic et al., 2020 [23] 9 days 3 days Due to the bleeding, the patient received one unit (325 ml) of pooled platelet concentrate with a one-hour post-transfusion platelet increase of 5,000/mm 3 (from 4,000/mm 3 to 9,000/mm 3 ). The patient was started on IVIG for a total of 1 g per kilogram of adjusted body weight (100 g), divided into two daily doses (50 g/day), and administered alongside intravenous dexamethasone 40 mg daily. On the third day of therapy, the platelet count started to rise. possibility of bias in reporting mild cases with a focus on reporting cases with a severe drop in platelet count.

This systematic review and meta-analysis have demonstrated that ITP secondary to COVID-19 infection was slightly more prevalent among males (54.8%) than females. The elderly population was more vulnerable to the disease as most of the cases were older than 50 years with a median age of 63 years. We also found that most cases developed ITP after COVID-19 infection within 2-3 weeks with an estimated mean time of 18.1 ± 21 days, and the estimated mean time to recovery from ITP was less than one week (5.8 ± 4.8) . Most patients in this study were treated with IVIG in variable doses, and dexamethasone and platelet unit transfusion usually failed. We also recorded a low mean platelet count in thrombocytopenic COVID-19 patients, which exposes them to a higher risk of complications. After excluding many concomitant causes or illnesses that can induce thrombocytopenia in COVID-19, the authors believe that a systematic approach is required to diagnose new-onset ITP. Clinicians should also be aware of multiple instances of ITP in COVID-19 patients in the post-recovery phase.

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Funding This paper was not funded.

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Mohammed Ghannam Alharbi http://orcid.org/0000-0002-4131-4749