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 Table of Contents  
Year : 2022  |  Volume : 5  |  Issue : 1  |  Page : 25-30

Reversible rheumatological syndrome with acute febrile respiratory illness secondary to COVID vaccination

1 Department of Pulmonary Medicine, MIMSR Medical College, Latur, Maharashtra, India
2 Department of Internal Medicine, MIMSR Medical College, Latur, Maharashtra, India

Date of Submission24-Apr-2022
Date of Decision13-May-2022
Date of Acceptance04-May-2022
Date of Web Publication12-Aug-2022

Correspondence Address:
Shital Patil
Department of Pulmonary Medicine, MIMSR Medical College, Latur, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/japt.japt_12_22

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Rheumatological manifestation with acute febrile respiratory illness known to occur after coronavirus disease 2019 (COVID-19) pneumonia and presenting as long COVID disease, its occurrence with COVID vaccination is not very well associated or described in the literature. In this case report, a 45-year-old female, presented with constitutional symptoms, persistent fever, and lung parenchymal infiltrates, without mycobacterial microscopic or genome documentation, received empirical anti-tuberculosis treatment with the progression of disease with little clinical or radiological response. Bronchoscopy workup was inconclusive and tropical screen for bacterial, fungal, Tuberculosis, and malignancy were negative. Vasculitis workup was inconclusive and rheumatological workup documented highly raised ANA titers. We have started her on steroid and hydroxychloroquine and clinical response documented with near-complete resolution of shadows in 12 weeks. Rheumatological syndrome which is a rare vaccine-related adverse event, reversible, and easily treatable with routinely available medicines and importantly, it is having excellent prognosis. Minimal systemic adverse events are known to occur with all viral vector vaccines, but its occurrence is rare and it should not impact on routine vaccinations; as vaccination is a key step in this pandemic to protect humankind.

Keywords: ANA test, bronchoscopy, COVID-19 pneumonia, febrile respiratory illness, rheumatological syndrome

How to cite this article:
Patil S, Narwade G, Acharya A. Reversible rheumatological syndrome with acute febrile respiratory illness secondary to COVID vaccination. J Assoc Pulmonologist Tamilnadu 2022;5:25-30

How to cite this URL:
Patil S, Narwade G, Acharya A. Reversible rheumatological syndrome with acute febrile respiratory illness secondary to COVID vaccination. J Assoc Pulmonologist Tamilnadu [serial online] 2022 [cited 2023 Jan 27];5:25-30. Available from: http://www.japt.com/text.asp?2022/5/1/25/353740

  Introduction Top

Vaccines as triggers of autoimmunity are a controversial subject. Many vaccine-related immunological adverse events have been described, for example, evidence for an increased risk of Guillain–Barré syndrome following influenza vaccine, an association between systemic lupus erythematosus and the papilloma vaccine, and episodes of immune demyelination after hepatitis B vaccine were all previously suggested.[1],[2] Although direct causation is debatable, the association is plausible. Detecting immunological adverse reactions to the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines is of great public and scientific interest. In this case report, we have documented reversible nature of rheumatological syndrome with febrile respiratory illness associated with the coronavirus disease (COVID) vaccine.

  Case Report Top

A 45-year-old female, housewife, no addiction history, normotensive, nondiabetic, referred to our center by a family physician for persistent fever, cough, and anorexia for 3 months of duration, received symptomatic treatment with antibiotics and antipyretics with no relief and her symptoms worsened during the mentioned period, and labeled her as perimenopausal symptoms, received supplementary treatment without any response. She was further evaluated for tuberculosis and treated empirically for tuberculosis also without documentation of acid-fast bacilli (AFB) or Mycobacterium tuberculosis (MTB) genome (sputum microscopy for AFB negative with sputum for GeneXpert MTB/rifampin [RIF] negative), shown the progression of anorexia with no responses to ATT (antituberculosis treatment).

Further clinical details

  1. Fever – intermittent, high grade without chills and rigors associated with minimal body ache, and headache
  2. Cough – dry, intermittent, with minimal white sputum production
  3. Loss of appetite and weight loss over 3 months
  4. Multiple small joints pain for 3 months
  5. Weakness and myalgia with fatigability
  6. Shortness of breath on exertion.

Clinical examination documented as:

Heart rate –100/minute, respiratory rate: 26/breath per minute.

PsO2: 90%–94% at room air resting and 88%–90% at room air on exertion.

Respiratory system examination revealed bilateral breath sounds diminished bilateral bases, bilateral crepitation on both lung fields.

Nervous system examination revealed higher functions normal, no neurological abnormality, cranial nerves normal, and recent and past memory normal recall.

Cardiovascular and gastrointestinal systems were normal.

We further asked for more history regarding the progression of disease over the past 3 months, her husband told regarding COVID vaccination (Covishield) was taken 1 month before the onset of symptoms. The patient disclosed that she was apparently asymptomatic before COVID vaccination (Covishield), and had a history of mild fever after the first dose of vaccination which was resolved after 1 week of vaccination, and she took the second dose of vaccine after 2 months, developed low-grade fever after 2nd week of vaccination, which was progressed over 4 weeks to have moderate-to-high grade, started on typical respiratory symptoms as cough with shortness of breath which was progressed over 3 months to present in the intensive care setting.

Laboratory examination documented as:

  • Hemoglobin –9.8 gram%, total white blood cells –20000/mm3, polymorphs –85%, and platelet count –490000/uL
  • CRP (C-reactive protein) –208 mg/L (0–6 mg/L), random blood sugar level –134 mg%, and HbA1C –5.60%
  • LDH (lactate dehydrogenase) – 980 IU/L (70–470 IU/L) and uric acid –3.4 mg (3.5–7.5 mg/dL)
  • Serum electrolytes: sodium –138 mEq/L (135–145 mEq/L), potassium –3.9 mEq/L (3.5–5.5 mEq/L), and ionic calcium –1.32 mEq/L (1.09–1.36 mEq/L)
  • D-dimer – 980 ng/ml (<500 ng/ml)
  • Interleukin 6 – 1.75 pg/ml (0.00–7.00 pg/ml)
  • RA factor – Negative
  • Anti-CCP – Negative
  • Thyroid functions – Normal
  • Liver and kidney functions – Normal.

Sputum examination for AFB was negative and TB GeneXpert MTB/RIF was negative for MTB genome.

COVID-19 reverse transcriptase–polymerase chain reaction test and results documented negative for SARS-CoV-2.

As clinical findings, electrocardiogram (ECG) is normal [Figure 2] and chest X-ray documented inhomogenous infiltrates in middle and lower zones in bilateral lung fields [Figure 1], we performed high-resolution computed tomography (HRCT) of the thorax.
Figure 1: Chest X-ray posteroanterior

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Figure 2: Electrocardiography

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High-resolution computed tomography thorax documented

The left upper lobe ground-glass opacifications (GGOs) with consolidation [Figure 3], middle and lower lobe GGOs and consolidation with increased interstitial opacities [Figure 4] and [Figure 5], right upper and middle lobe GGOs [Figure 4], [Figure 5], [Figure 6], and bilateral pleural effusion [Figure 7] and [Figure 8].
Figure 3: High-resolution computed tomography thorax showing left upper lobe GGOs

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Figure 4: High-resolution computed tomography thorax showing upper lobe consolidations

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Figure 5: High-resolution computed tomography thorax showing increased interstitial opacities in left lower lobe

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Figure 6: High-resolution computed tomography thorax showing left upper lobe, lingula and right lower lobe GGOs

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Figure 7: High-resolution computed tomography thorax showing bilateral pleural effusion

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Figure 8: High-resolution computed tomography thorax showing left pleural effusion

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As HRCT was showing lung parenchymal abnormality with predominant acinonodular opacities bilaterally, we have performed fiberoptic video-bronchoscopy as sputum examination was inconclusive.

Bronchoscopic examination revealed hyperemic mucosa at the lower trachea, carina with purulent secretions coming out from bilateral main stem bronchial lumens, increased rugosity in segmental bronchial openings, without any endobronchial, submucosal, and peribronchial visible abnormalities. Bronchoalveolar lavage (BAL) was collected after 100 ml saline instillation and four aliquots were sent for cytology, GeneXpert, and bacterial and fungal culture.

  • BAL cytology suggestive of acute inflammation, negative for malignant cell
  • BAL AFB – Negative
  • BAL GeneXpert MTB/RIF – Negative
  • BAL bacterial culture – No growth
  • BAL fungal culture – No growth.

As tropical workup and lung malignancy workup was negative in the presence of positive bronchus sign on HRCT thorax, we have analyzed further for rheumatological and vasculitis workup.

  • MPO (Myeloperoxidase) Test (P-ANCA)- 0.75 RU/ml (normal range 0–20 RU/ml)
  • PR3 (proteinase-3) test (C-ANCA) was 0.86 RU/ml (normal range 0–20 RU/ml).
  • ANA – Speckled and nucleolar pattern, 1:1000 titer
  • dsDNA – Negative
  • ANA BLOT – Negative (dsDNA, nucleosomes, histones, SmD1, PCNA, P0, SS-A/Ro60kD, SS-A/Ro52kD, SS-B/La, CENP-B, Scl-70, U1 snRNP, AMA M2, Jo-1, Pm-Scl, Ku, and Mi-2 in serum).

Cardiac workup as:

  • NT-Pro-BNP – 115 Pg/ml (<125 pg/ml exclusion of nonacute heart failure)
  • Trop-I –10 ng/ml (normal <19 ng/ml)
  • CPK-MB test (creatine phosphokinase-MB) –9 ng/ml (normal <25 IU/L).

Two-dimensional echocardiography-suggestive of normal left ventricular systolic function, type I left ventricular diastolic dysfunction, normal chambers, normal valves, no regional wall motion abnormality, and no pulmonary hypertension.

The patient was having febrile respiratory illness with leukocytosis and minimal bilateral pleural effusion, we have done USG thorax for possible aspiration, but it was found difficult to aspirate to differentiate infective etiology or culture if possible.

Treatment was initiated with higher antibiotics such as injection meropenem 1 gm IV TDS, injection teicoplanin 400 mg IV OD, injection methylprednisolone 40 mg IV TDS, antipyretics for fever control, adequate oral liquids with intravenous fluids, and maintained hydration with Kidney functions and liver functions tests monitoring. After 1 week, HRCT thorax and other laboratory investigations were repeated.

HRCT thorax suggestive of minimal GGOs bilaterally, no consolidation [Figure 9] and [Figure 10], with complete resolution of bilateral pleural effusion [Figure 11] and [Figure 12].
Figure 9: High-resolution computed tomography thorax

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Figure 10: High-resolution computed tomography thorax

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Figure 11: High-resolution computed tomography thorax

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Figure 12: High-resolution computed tomography thorax

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After 1 week, injectable methylprednisolone has been shifted to oral and dose decrease from 40 mg TDS to oral 48 mg and tapered over 12-weeks. We have added hydroxychloroquine 400 BD for 1 month then 400 OD for 12 weeks.

Repeated chest X-ray posteroanterior after 12 weeks of treatment, showing near-normal lung parenchyma with both CP angles clear [Figure 13].
Figure 13: High-resolution computed tomography thorax

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After 3 months, we have repeated ANA titer, liver and kidney functions, with routine hemogram and other tests and documented all parameters in the normal range.

ANA test-negative

We have continued hydroxychloroquine 200 mg OD for more 3 months and then stopped all medicines thereafter. We are following for any rheumatological symptoms in the past 6 months and documented as symptoms with pathology near-complete reversed with all vital parameters in normal.

  Discussion Top

At the end of 2019, COVID-19 was first reported in Wuhan, China, triggered by SARS-CoV-2, and has swiftly spread worldwide. The COVID-19 pandemic caused by SARS-CoV-2 has led to an unprecedented setback for global economy and health. Vaccination is one of the most effective interventions to substantially reduce severe disease and death due to SARS-CoV-2 infection. To date, treatments for COVID-19 are mainly targeted symptomatic treatment and supportive therapy. Currently, one of the most effective strategies for mitigating the COVID-19 pandemic is global vaccination that can create an immune barrier among population to attenuate the speed and scope of SARS-CoV-2 transmission.

The two most common COVID-19 vaccine platforms currently in use, including mRNA (i.e., Pfizer-BioNTech and Moderna) and adenovirus vector (i.e., Johnson and Johnson and AstraZeneca), elicit robust humoral responses and have shown safety in the majority of populations vaccinated.[3]

However, as vaccination programs are being rolled out globally, many COVID-19 vaccine-related side effects have been recently reported,[4],[5] ranging from mild local symptoms (e.g., pain at the injection site) to systemic symptoms (e.g., fever and/or headache).[6] Localized pain, fatigue, headache, and muscle ache are the most prevalent adverse effects in patients with autoimmune and inflammatory rheumatic diseases following six COVID-19 vaccines.[7] Previous studies indicated that human papillomavirus, hepatitis B, and influenza vaccines may trigger the onset or exacerbations of autoimmune diseases by molecular mimicry inducing autoimmunity.[2],[8]

Once mRNA vaccine is injected, the mRNA enters muscle cells, and the ribosomes perform cellular translation producing the spike protein, a viral receptor-binding domain that recognizes and binds to the host receptor angiotensin-converting enzyme 2. Subsequently, a robust CD8+ and CD4+T-cell-mediated response are triggered and eventually induces the production of neutralizing antibodies and memory T and B cells.[9] As for adenoviral vector vaccines, SARS-CoV-2 antigens were delivered by viral vector to invade the cell. The virus vector is physically or chemically weakened and therefore does not cause disease.[10] Within the host cell, the SARS-CoV-2 spike protein antigen is expressed and triggers T-cell-mediated immune response.[11],[12] There are two leading viral vector vaccines currently in use including Janssen adenovirus-based vaccine and AstraZeneca adenovirus-based vaccine (ChAdOx1 nCoV-19). There are currently 17 nonreplicating and two replicating viral vector candidate SARS-CoV-2 vaccines in clinical development.[13] The former has been approved by regulatory authorities globally for emergency use.[14]

New-onset autoimmune manifestations following COVID-19 vaccination are being reported extensively.[15],[16],[17] The main mechanisms through which the COVID-19 vaccine triggers autoimmunity include molecular mimicry, the production of particular autoantibodies, and the role of certain vaccine adjuvants. Previous studies have revealed that SARS-CoV-2 infection could trigger autoimmunity,[18] but the association between COVID-19 vaccine and autoimmune phenomena remains nebulous. The respiratory system presented as the first organ invaded by SARS-CoV-2, which may be involved in the cross-reactions between the immune response after SARS-CoV-2 infection and pulmonary surfactant proteins, because the SARS-CoV-2 spike glycoprotein and lung surfactant proteins shared 13 of 24 pentapeptides.[19] In addition, the cross-reaction between SARS-CoV-2 proteins and a variety of tissue antigens could lead to autoimmunity against connective tissue and the cardiovascular, gastrointestinal, and nervous systems.[20] Infections act as environmental triggers to cause autoimmune diseases triggered by vaccines, while microbial antigens can elicit cross-reactive immune responses against self-antigens.[9] The immune cross-reactivity triggered by the similarity between certain vaccine components and specific human proteins could render the immune system against pathogenic antigens to attack similar proteins in susceptible population and lead to autoimmune diseases, a process known as molecular mimicry. Influenza, hepatitis B, and human papillomavirus vaccines have been suspected to trigger autoimmunity through molecular mimicry.[2],[20] In addition, only a minority of vaccinated subjects subsequently developed autoimmune phenomena, indicating a genetic predisposition to vaccine-induced autoimmunity.

Table showing different new-onset autoimmune phenomena following diverse COVID-19 vaccines[21]

In the present case report, we have documented as reversible nature of rheumatological syndrome and shown an excellent response to steroids and hydroxychloroquine.

Key learning points from this case report are:

  1. Rheumatological syndrome is known to occur after COVID pneumonia and now data is available its association with COVID vaccination
  2. Although rheumatological syndrome that occurs with COVID-19 pneumonia is not totally reversible or many cases showing persistent nature, we have documented reversible nature as its association with COVID vaccination in our case
  3. Febrile respiratory illness is a typical manifestation of infective etiology in tropical seating like India ranging from bacterial, atypical organisms, viral, and TB. In COVID-19 pneumonia typical presentation as “acute febrile respiratory illness” is relatively less common, and it has been well-documented after vaccination
  4. Persistent constitutional symptoms and poor response to antituberculosis treatment is clinical clue toward to rule out other etiological factors for similar syndromic presentation. Bilateral pleural effusion with parenchymal infiltrates is radiological clue toward the viral or immunological nature of disease
  5. Although the ANA test is not confirmatory and specific to rule out rheumatological syndrome, its high titer signifies toward immune nature of disease. ANA blot panel is more specific to label inexact nature of autoimmune disease
  6. Steroids are cornerstone of the treatment of rheumatological syndrome with lung involvement and shown excellent response to steroids with hydroxychloroquine. Echocardiography is must in all cases to rule out cardiac dysfunction before initiation of treatment
  7. We recommend all cases with febrile respiratory illness with a history of COVID vaccination should undergo prompt evaluation to rule out rheumatological nature of disease
  8. Rheumatological syndrome which is a rare vaccine-related adverse event, and importantly, it is reversible and managed with routinely available medicines and is having an excellent prognosis
  9. Minimal systemic adverse events are known to occur with all viral vector vaccines, but its occurrence is rare and it should not impact on routine vaccinations; as vaccination is a key step in this pandemic to protect humankind.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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Segal Y, Shoenfeld Y. Vaccine-induced autoimmunity: The role of molecular mimicry and immune crossreaction. Cell Mol Immunol 2018;15:586-94.  Back to cited text no. 2
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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13]


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