新冠長期症狀(Long COVID)在 HIV 感染者中更常見

資料來源：基思·奧爾康 / 2022 年 3 月 7 日 / aidsmap news；財團法人台灣紅絲帶基金會編譯

圖片來源：Bits And Splits/Shutterstock.com.

加州大學 HIV 研究人員進行的一項小型研究表明，未接種疫苗的 HIV 感染者在急性 COVID-19 疾病後出現「新冠長期症狀」的可能性是 HIV 陰性者的四倍，這些症狀與較高水準的發炎性標誌物有關，加州大學舊金山分校的研究者在一項小型研究中發現。在同儕審查之前，該研究已以預印本提供。

該研究的作者之一 Steven Deeks 教授在反轉錄病毒和伺機性感染會議 (CROI 2022)上表示有關新冠長期症狀，慢性炎症的存在伴隨著免疫功能紊亂可能會導致更高的風險——但所有小組成員在會議中承認，關於導致這種情況的原因還需要進一步了解。 Deeks 說，數據顯示，COVID-19 患者應在首次出現症狀時積極接受治療，以降低病毒水準並最大限度地降低新冠長期症狀的風險。

“Long COVID”是一個標幟，適用於在某些人由 SARS-CoV-2 引起的急性疾病後持續數月或數年的一系列異質症狀。除了持續咳嗽、發燒、疲勞和呼吸急促外，有新冠長期感染症狀的人可能會報告認知功能障礙（「腦霧」）、嗅覺喪失、注意力不集中、失眠、關節和肌肉疼痛、頭暈或心悸。

英國的一項大型研究發現，在具COVID症狀者感染後三到四個月，大約 5% 的人仍然有症狀——如果人們在三個月後仍未康復，症狀往往會持續存在。老年人、女性、有既往疾病或身體質量指數(BMI)較高的人以及社會經濟地位較低的人有新冠長期症狀的風險較高。更嚴重的急性感染也是一個危險因素。接種疫苗可降低出現新冠長期症狀的風險。

加州大學舊金山分校的研究比較了 39 名在接種疫苗前感染並從 COVID-19 中恢復的 HIV 感染者之免疫系統標誌物和症狀，以及一個由年齡、性別、COVID-19 住院史和感染後的時間等相匹配的 43 名 HIV 陰性對照組。

HIV 感染者的中位年齡為 54 歲，95% 為男性，38% 為白人，36% 為西班牙裔，18% 為黑人/非裔美國人，5% 為太平洋島民。四分之一 (26%) 是當前吸煙者。與 HIV 陽性參與者相比，HIV 陰性對照組的參與者更多是白人（60%），而當前吸煙者則更少（2%）。

研究參與者很少有嚴重的 COVID-19 病史。只有 13% 的 HIV 感染者和 17% 的 HIV 陰性參與者住院，每組中只有一個人需要機械式通氣。沒有人接受過專門針對 COVID-19 的治療（所有人都在 2020 年 12 月之前住院）。

在這項研究中，被標示為新冠長期症狀 (long COVID) 或新冠後急性後遺症 (post-acute sequelae of SARS-CoV-2, PASC) 被定義為在感染SARS-CoV-2 後其COVID-19的症狀仍持續出現6週以上。但不包括在 COVID-19 感染之前出現的症狀。

參與者在 SARS-CoV-2 檢測呈陽性後大約四個月（中位 124 天）接受了症狀和免疫學評估。在愛滋病毒感染者的評估訪查中，最常報告的新症狀或惡化症狀是疲勞 (42%)、肌肉疼痛 (24%)、注意力不集中 (42%)、視力問題 (21%) 和睡眠困難 (34%)；與對照組相比，愛滋病毒感染者報告這些症狀的頻率大約是對照組的兩倍。兩組出現呼吸急促、流鼻涕、心悸、胃腸道不適和頭暈的頻率相似（每例均<20%）。

所有感染 HIV 的參與者都接受了抗反轉錄病毒治療，除了兩個之外所有參與者的病毒載量都檢測不到，CD4 細胞計數中位數為 596（與 HIV 陰性參與者的中位數計數沒有顯著差異）。

免疫學分析顯示 HIV 感染者和 HIV 陰性對照組之間存在一些差異。 HIV 感染者的 SARS-CoV-2 特異性記憶 CD8+ T 細胞水準降低了 70%，而 SARS-CoV-2 特異性記憶 CD4+ T 細胞上的 PD-1 表達水準更高。較低的 CD8+ T 細胞水準可能顯示未來對 SARS-CoV-2 感染的反應能力降低。更大的 PD-1 表達可能顯示，如果這些 CD4 細胞再次遇到病毒，它們對 SARS-CoV-2 的反應效率會降低。然而，與 HIV 陰性對照組相比，HIV 感染者的抗體反應並沒有降低。

HIV 感染者的 CD4/CD8 比值之中位數顯著降低（0.94 vs 2.0）； HIV 感染者中較低水準的CD4/CD8 比值與較高的SARS-CoV-2 PD-1 表達有關。 CD4/CD8 比值低在 CD4 計數低於 500 的人群中更為常見。研究人員表示，這一發現顯示早期抗反轉錄病毒治療和病毒的抑制對於保存 HIV 感染者之免疫功能以對應廣泛感染之重要性（包括 SARS-CoV-2 ）。 

當檢視 HIV 狀態與新冠長期症狀的存在和免疫標記之間的關係，發現 HIV 感染者出現新冠長期症狀的可能性是其四倍。當新冠長期症狀被定義為三個或更多之症狀時，愛滋病病毒感染者報告它的可能性是 2.72 倍。

抗體或 T 細胞對 SARS-CoV-2 的反應與症狀的存在之間沒有關係，但 CD4+ 記憶 T 細胞上更高水準的 PD-1 表達確實預測了新冠長期症狀的存在。為什麼 PD-1 水準會與新冠長期症狀相關仍不清楚。作者推測，較高的 PD-1 水準可能顯示更多地暴露於 SARS-CoV-2 抗原之跡象，而並非顯示是 CD4 細胞對未來感染的功能降低。

HIV 感染者的幾種炎症標誌物（IL-6、TNF-α 和 IP-10）水準較高，而較高水準的 IP-10 和 IL-6 與新冠長期症狀的風險增加有關。

研究人員說，需要對 HIV 感染者的新冠長期症狀之 頻率進行更大規模的研究，尤其是在女性和免疫功能較差的人群中。

新冠長期症狀的治療應包括復健和物理治療、抗憂鬱藥、補充劑和益生菌，以及針對該症候群特定方面之試驗性使用藥物。

但基於多項研究的證據顯示，新冠長期症狀與急性感染中較高的病毒水準有關，Deeks 教授說：「 隨著這種病毒成為地方病，仍然有理由使用抗體和抗病毒藥物非常積極地治療人們 […] .根據我們所知道的一切，這應該會大大降低發展為長期併發症的風險」。

參考文獻：

Peluso M et al. Post-acute sequelae and adaptive immune responses in people living with HIV recovering from SARS-CoV-2 infection. MedRxiv, published online 14 February 2022.

Deeks S. Putting Long COVID in context. Session: Long COVID – From Bench to Bedside and Beyond. Conference on Retroviruses and Opportunistic Infections, 2022.

Long COVID more common in people with HIV

Keith Alcorn / 7 March 2022 / aidsmap news

Bits And Splits/Shutterstock.com. Image is for illustrative purposes only.

Unvaccinated people with HIV were four times more likely than HIV-negative people to experience ‘long COVID’ symptoms after acute COVID-19 illness and these symptoms were associated with higher levels of inflammatory markers, a small study conducted by HIV researchers at University of California San Francisco has found.

The study has been made available as a pre-print, prior to peer review.

Professor Steven Deeks, one of the authors of the study, told a Conference on Retroviruses and Opportunistic Infections (CROI 2022) session on long COVID that the presence of chronic inflammation alongside disturbed immune function may contribute to the higher risk – but all panellists in the session admitted that there is still much to learn about what causes the condition. Deeks said the data suggest that people with COVID-19 should be aggressively treated at the time they first develop symptoms to reduce virus levels and minimise the risk of long COVID.

‘Long COVID’ is a label applied to a heterogenous array of symptoms that persist in some people for months or years after an acute illness caused by SARS-CoV-2. As well as persistent cough, fever, fatigue and shortness of breath, people suffering from long COVID may report cognitive dysfunction (‘brain fog’), loss of smell, difficulty in concentrating, insomnia, joint and muscle pain, dizziness or palpitations.

A large UK study found that three to four months after developing COVID, around 5% of people still had symptoms – and that if people had not recovered after three months, the symptoms tended to persist. The risk of long COVID was higher in older people, women, people with pre-existing conditions or high body mass index and in people of lower socioeconomic status. More severe acute infection was also a risk factor. Vaccination reduces the risk of long COVID symptoms.

The University of California San Francisco study compared immune system markers and symptoms in 39 people with HIV recovering from COVID-19 contracted prior to vaccination and an HIV-negative control group of 43 people matched by age, sex, history of hospitalisation for COVID-19 and time since infection.

Participants with HIV had a median age of 54 years, 95% were male, 38% White, 36% Hispanic, 18% Black/African American and 5% Pacific Islander. One in four (26%) was a current smoker. Participants in the HIV-negative control group were more often White (60%) and less often current smokers (2%) than the HIV-positive participants.

A history of severe COVID-19 was rare in study participants. Only 13% of people with HIV and 17% of HIV-negative participants had been hospitalised and only one person in each group had required mechanical ventilation. None had received specialised treatments for COVID-19 (all were hospitalised before December 2020).

In this study, long COVID, or post-acute sequelae of SARS-CoV-2 (PASC) as it is labelled, was defined as the presence of COVID-19 symptoms more than six weeks after SARS-CoV-2 infection. Symptoms that were present before COVID-19 were not included.

Participants underwent symptom and immunological assessment approximately four months after testing positive for SARS-CoV-2 (median 124 days). The most commonly reported new or worsening symptoms at the assessment visit in people with HIV were fatigue (42%), muscle pain (24%), concentration problems (42%), vision problems (21%) and trouble sleeping (34%). Each of these symptoms was approximately twice as frequently reported by people with HIV compared to the control group. Shortness of breath, runny nose, palpitations, gastrointestinal complaints and dizziness occurred at similar frequencies in both groups (< 20% in each case).

All participants with HIV were on antiretroviral treatment, all but two had undetectable viral loads and the median CD4 cell count was 596 (not significantly different from the median count in HIV-negative participants).

Immunological analysis showed several differences between people with HIV and the HIV-negative control group. People with HIV had 70% lower levels of SARS-CoV-2-specific memory CD8+ T cells and higher levels of PD-1 expression on SARS-CoV-2-specific memory CD4+ T cells. Lower CD8+ T cell levels may indicate reduced capacity to respond to SARS-CoV-2 infection in the future. Greater PD-1 expression may indicate that these CD4 cells will be less efficient in responding to SARS-CoV-2 if they encounter the virus again.

However, people with HIV did not have reduced antibody responses when compared to the HIV-negative control group.

Participants with HIV had a significantly lower median CD4/CD8 ratio (0.94 vs 2.0); a higher CD4/CD8 ratio in people with HIV was associated with lower levels of SARS-CoV-2 PD-1 expression. A low CD4/CD8 ratio is more common in people with CD4 counts below 500. The researchers say this finding shows the importance of earlier antiretroviral treatment and viral suppression for preserving immune function against a wide range of infections in people with HIV, including SARS-CoV-2.

Looking at the relationship between HIV status, the presence of COVID-19 symptoms and immunological markers, the researchers found that people with HIV were four times more likely to have long COVID symptoms. When long COVID was defined as three or more symptoms, people with HIV were 2.72 times more likely to report it.

There was no relationship between antibody or T-cell responses to SARS-CoV-2 and the presence of symptoms, but higher levels of PD-1 expression on CD4+ memory T cells did predict the presence of long COVID. Why PD-1 levels should correlate with long COVID symptoms remains unclear. Rather than indicating reduced CD4 cell function against future infection, higher PD-1 levels might be a sign of greater exposure to SARS-CoV-2 antigen, the authors speculate.

People with HIV had higher levels of several inflammatory markers (IL-6, TNF-alpha and IP-10) and higher levels of IP-10 and IL-6 were associated with an increased risk of long COVID symptoms.

The researchers say larger studies of long COVID frequency in people with HIV are needed, especially in women and people with poorer immune function.

Treatment for long COVID may include rehabilitation and physical therapy, antidepressants, supplements and probiotics, as well as experimental use of pharmaceutical drugs to target particular aspects of the syndrome.

But based on evidence from several studies that long COVID is associated with higher virus levels in acute infection, Professor Deeks said: “As this virus becomes endemic, there’s still going to be a reason to treat people very aggressively […] with antibodies and antivirals. Based on everything we know, that should substantially reduce the risk of developing long-term complications.”

References

Peluso M et al. Post-acute sequelae and adaptive immune responses in people living with HIV recovering from SARS-CoV-2 infection. MedRxiv, published online 14 February 2022.

Deeks S. Putting Long COVID in context. Session: Long COVID – From Bench to Bedside and Beyond. Conference on Retroviruses and Opportunistic Infections, 2022.。”