During its peak, the coronavirus disease 2019 (COVID-19) pandemic threatened to overwhelm entire healthcare systems; thus, many governments wisely chose to prioritize keeping the pandemic under control, albeit at the expense of maintaining care for diseases that require less urgent attention. As widespread vaccination programs arise in 2021, medical researchers are beginning to turn their attention towards the impact of the COVID-19 pandemic on other diseases in areas such as diagnosis, treatment, and prognosis. 

It can be argued that the COVID-19 pandemic resulted in compromises all around, especially in elective and home care. It was as if the whole medical world stopped to plug the bleed caused by the pandemic; only as the threat of the pandemic began to subside did we stop to count the cost. 

COVID-19 adversely impacted healthcare in 2 major ways: first, it drained resources from other illnesses that are arguably equally life-threatening in nature; second, it interacted with existing illnesses to cause a myriad of symptoms never seen before. Furthermore, the pandemic laid bare the vulnerabilities of patients with chronic illnesses who were otherwise stable. 

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There is no doubt that once the pandemic is over, the aftermath will be prolonged and yield interesting findings. Researchers are already looking into how COVID-19 has interacted with the pathophysiology of known diseases. In a letter to the editor in the Annals of Hematology, a group of researchers described 2 case studies involving cold agglutinin disease (CAD) associated with COVID-19.

Case Study 1 

A 43-year-old woman presented with generalized weakness, fever, cough, diarrhea, and shortness of breath. Her symptoms lasted for 10 days. Listed below are findings obtained from history-taking and medical investigations: 

  • History of obesity and untreated multiple sclerosis
  • Nasopharyngeal reverse transcription-polymerase chain reaction (RT-PCR) confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection
  • Chest computed tomography revealed atypical severe interstitial pneumonia
  • Normal hemoglobin levels upon admission (13.1 g/dL)

The patient was treated with oxygen support and prescribed a course of antibiotics (ceftriaxone and azithromycin for 3 days, tazocillin for the 3 days after). Her respiratory parameters improved rapidly. 

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On day 6, the patient’s condition deteriorated. Below are the results of the medical investigations conducted: 

  • Decreased hemoglobin levels (6.1 g/dL)
  • Hemolytic features were present – low haptoglobin, elevated bilirubin, elevated lactate dehydrogenase (LDH)
  • Positive direct antiglobulin test (4+) with the presence of cold agglutinins
  • Etiological workup for hemolysis returned negative

The patient was given blood transfusions. After poor initial transfusion efficiency, her hemoglobin levels and hemolytic parameters were observed to have improved.

Case Study 2 

A 63-year-old man was admitted to the intensive care unit for severe acute respiratory syndrome. He complained of fever, cough, and progressive dyspnea for the previous 2 weeks. He had a medical history of hypertension.

Below are the results of the medical investigations conducted: 

  • Nasopharyngeal RT-PCR confirmed SARS-CoV-2 infection
  • Blood count showed nonregenerative normocytic anemia (hemoglobin, 10.5 g/dL)
  • Haptoglobin levels were unmeasurable (<0.08 g/L)
  • Increased serum orosomucoid (2.35 g/L)
  • Positive direct antiglobulin test (C3 [4+] and IgG [2+]) with the presence of cold agglutinins

On day 6, the patient’s hemoglobin levels dropped to 8.2 g/dL. The etiological workup was negative. Within 9 days, his hemoglobin levels improved, as did his clinical condition. 

Treating CAD Exacerbated by COVID-19

Usually, when CAD is associated with a viral infection, it is linked to Mycoplasma pneumonia infection or Epstein-Barr virus. These case studies demonstrate that CAD can likewise be associated with SARS-CoV-2 infection.

Although the 2 case studies described did not indicate the use of any immunosuppressive therapy, there are cases of patients with CAD deteriorating significantly when coinfection with COVID-19 was discovered. Because so little is known about COVID-19, clinical decision-making then becomes all the more difficult.

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How does COVID-19 complicate efforts to treat CAD? According to Ahmed et al, “In the context of COVID-19, B-cell depletion can impair the development of neutralizing anti-SARS-CoV-2 antibodies, increasing the risk of infection and impaired vaccine efficacy.” For example, research has shown that patients with a disease of inflammatory of rheumatological origin have a higher severity of COVID-19 illness after exposure to rituximab. Scientists are still unsure if this is due to the rituximab treatment itself or to COVID-19. Nevertheless, it bodes ill for diseases like CAD in which rituximab is considered first-line therapy. 

Therapeutic plasma exchange (TPE) has been used as a temporizing treatment in CAD patients with COVID-19. TPE is usually reserved for CAD patients with fulminant hemolytic anemia, and it is a temporary solution that must be used in combination with immunosuppressive therapy. However, in the extraordinary circumstance of a pandemic, TPE can be used to buy time for the patient to recover from COVID-19. 

Into the Unknown 

This article attempts to demonstrate the difficulties of treating a known illness in exceptionally murky circumstances. In the early days of the COVID-19 pandemic, we knew 2 things for sure: it was a highly infectious disease, and its mortality rate, though low, was sufficient to cripple healthcare systems if nothing was done. How it interacted with the immune system, especially in autoimmune diseases, was anyone’s guess. 

Eventually, research will solidify our knowledge of these matters. However, physicians having to treat patients with COVID-19 and other chronic illnesses in real time had to be extraordinarily cautious in the face of an unpredictable global pandemic. Physicians are used to relying on established protocols in making clinical decisions, but what happens when that isn’t available? In these instances, good sense, interdisciplinary dialogue, and patience can make a big difference. 


Huscenot T, Galland J, Ouvrat M, Rossignol M, Mouly S, Sène D; APHP Lariboisière COVID Group. SARS-CoV-2-associated cold agglutinin disease: a report of two cases. Ann Hematol. 2020;99(8):1943-1944. doi:10.1007/s00277-020-04129-9

Ahmed Y, Khandelwal A, Walker L. Cold agglutinin disease and COVID-19 requiring therapeutic plasma exchange. BMJ Case Rep. 2021;14(7):e244227. doi:10.1136/bcr-2021-244227