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Case Report
Open Access Peer-reviewed

Differential Diagnosis in the Age of COVID-19 and the Need to Maintain a Broad Differential

Amandeep S. Saini, Jacob Schwartz
American Journal of Medical Case Reports. 2021, 9(1), 62-64. DOI: 10.12691/ajmcr-9-1-15
Received October 21, 2020; Revised November 02, 2020; Accepted November 08, 2020

Abstract

During the coronavirus pandemic, patients admitted to emergency departments (ED) with constitutional symptoms, respiratory complaints, and/or history of sick contacts have high clinical suspicion for COVID-19 regardless of whether initial screening tests are negative. Although communities seek daily coronavirus infection rates of less than one percent, physicians can be highly focused on narrow differentials despite adequate history and physical exams. This case report focuses on an elderly patient with a past medical history of hypertension, chronic kidney disease (CKD), and gout who presented with three days of fevers, chills, body aches, and shortness of breath and reported a home oxygen saturation of 89%. The patient was a health care worker with high risk of contracting COVID-19, and on admission was febrile and found to have lymphopenia. Nevertheless, COVID-19 Polymerase Chain Reaction (PCR) testing returned negative on two separate occasions prompting the team to broaden their differential. Leukopenia, thrombocytopenia and mildly elevated transaminases can all be due to COVID-19, but should also lead medical teams to include tick-borne illnesses as a potential etiology. Parasite serology returned positive for Babesia microti via IgG antibodies (1:512) and Anaplasma phagocytophilum via PCR and the patient was discharged on appropriate antimicrobial therapy. It is important for providers to understand and recognize the following: 1) overlapping symptoms of tick-borne disease and COVID-19, 2) proper diagnosis and management of babesiosis and anaplasmosis, and 3) benefits of broad differentials for patient care during the COVID-19 pandemic.

1. Introduction

In the United States a surveillance report to the Centers for Disease Control revealed a range of symptoms associated with COVID-19: cough in 50%, fever (subjective or > 100.4°F) in 43%, myalgia in 36%, headache in 34%, dyspnea in 29%, sore throat in 20%, diarrhea in 19%, nausea/vomiting in 12%, anosmia/ageusia in 10% 1. The variety of possible symptoms along with inquiries about travel history and sick contacts may cause premature bias and mislabel cases as COVID-19 despite negative screening tests results. Certainly, false negative nasopharyngeal swabs have ultimately returned positive in some cases 2, 3. In communities with declining rates, however, efforts should be taken to broaden patient differential diagnoses. Key geographical regions during the summer months are known for tick-borne diseases and can present with similar symptoms described above. Here we report a case of a 61-year-old male with a past medical history of hypertension, CKD, and gout who presented with three days of fever, chills, body aches, and complaints of shortness of breath, possibly indicating COVID-19, but was found to have B. microti coinfection with A. phagocytophilum.

2. Case Presentation

A 61-year-old male with a past medical history of hypertension, CKD, and gout presented with three days of fever (up to 103 °F), chills, body aches, and reported shortness of breath. He reported a home oxygen saturation of 89% via pulse oximeter. The patient was a healthcare worker who had been working during the pandemic and up until his ED arrival. Of note, the patient’s wife is also a healthcare worker and tested positive for COVID-19 three months prior; however, the patient claimed he tested negative on two separate occasions. The patient had known recent travel outside of New York State and known sick contacts aside from his wife for the past three months.

On presentation, he was febrile at 101.4 °F, heart rate 88, blood pressure 116/77, breathing 18 breaths per minute, and saturating 97% on room air. On physical exam, the patient was resting comfortably without nasal discharge and had clear breath sounds and no accessory muscle use. His skin was warm and dry and no rashes were noted on the extremities. Shown in Table 1 are his pertinent admission labs. His venous blood gas (VBG) was unremarkable with a pH of 7.37 and pCO2 of 36. The urinalysis was notable for trace protein, small blood, and bacteria despite no white blood cells. Blood and urine cultures returned negative for growth. Initial COVID-19 PCR testing from the ED was negative. Lower extremity duplex ultrasound was done for elevated D-Dimer and did not show venous thrombosis. On the second day of admission a repeat COVID-19 PCR was sent, and the patient’s labs were notable for the following: leukopenia (3.48 K/μL; normal 3.80-10.50 K/μL), thrombocytopenia (113 K/μL; normal 150-400 K/μL), and mildly elevated transaminases (AST 47 U/L, normal 10-40 U/L; ALT 59 U/L, normal 10-45 U/L).

Given that the second consecutive COVID-19 test returned negative, in conjunction with continuously high fevers and the aforementioned lab abnormalities, the primary team broadened their differential and interviewed the patient again. Further history revealed that the patient owned a home in Long Island, NY and was splitting his time between there and New York City during the pandemic. Moreover, he had done extensive yard work days before symptom onset. Based on this information a tick-borne workup was pursued for A. phagocytophilum, B. microti, Borrelia burgdorferi, and Ehrlichia chaffeensis. The patient was empirically dosed with doxycycline 100 mg twice a day, atovaquone 750 mg daily, and azithromycin 500 mg daily with clinical improvement in fevers and labs over the next 48 hours. Serology ultimately returned positive for B. microti with serum IgG ratio 1:512 and A. phagocytophilum via PCR (no Anaplasma antibodies). On the day of discharge, he was afebrile and saturating 99% on room air. He was sent home on a 10-day course of appropriate antimicrobial therapy and set up with outpatient follow up with an infectious disease expert.

3. Discussion

This case highlights the need to maintain a broad differential diagnosis even with COVID-19 related symptoms. Initially, the patient was admitted to a COVID-19 unit for acute hypoxic respiratory failure, despite having appropriate oxygen saturation and no respiratory distress on room air. While the patient was empirically started on azithromycin, there was no consideration for tick-borne disease until 36 hours into admission when collateral history revealed Long Island travels and recent yard work. This delay in proper management has the potential to compromise patient care in more severe cases. COVID-19 certainly remains a public health crisis, but clinical reasoning skills should not be limited by the pandemic.

Babesiosis and anaplasmosis should be suspected in the setting of relevant epidemiologic exposure, tick season, typical clinical manifestations, and laboratory test abnormalities. As with this patient, most infections with B. microti and A. phagocytophilum are acquired between the months of May and September. Babesia coinfection with Lyme disease, Ehrlichiosis, and human granulocytic anaplasmosis can occur due to transmission by the same Ixodes tick vector and was evident on this patient’s positive PCR result for A. phagocytophilum 4. One article evaluated co-infection rates across multiple studies, but the data remains significantly varied 5.

Common complaints of Babesiosis include fever, fatigue, chills, myalgia, headaches, and dry cough - a constellation of symptoms that can mimic those of COVID-19. Atypical physical findings may demonstrate scleral icterus, jaundice, and mild pharyngeal erythema 6. Rash is rarely seen, but if so, concurrent Lyme disease should be suspected. Laboratory abnormalities may reveal leukopenia, hemolytic anemia, thrombocytopenia, and/or elevated aminotransferases.

Human granulocytic anaplasmosis (HGA) is commonly caused by A. phagocytophilum, which was formerly known as E. phagocytophila and E. equi. Data from 2008-2012 revealed an annual incidence of anaplasmosis of 6.3 cases per million in the United States 7. Analogous to Babesiosis, most patients are febrile and develop nonspecific constitutional symptoms. In a small study of 18 adults with HGA, fever appeared an average of 5.5 days after a tick bite was noticed 8. Not surprising, both anaplasmosis and babesiosis share similar geographical prevalence and result in leukopenia, elevated aminotransferases, and thrombocytopenia. Rash is a rare finding in HGA, as evident in a retrospective case study that showed positive finding in 1 of 41 patients 9.

Diagnostic tools for babesiosis and anaplasmosis include blood smear (tetrad-forms/Maltese Cross and morulae, respectively), PCR, and serology. In our patient, IgG titers were 1:512. In the acute phase, B. microti IgG titers usually exceed 1:1024, but typically decline to ≤1:64 within 6 to 12 months 10. IgM antibody is typically detected two weeks after illness onset and the correlation between titers and symptoms is poor 11. Unfortunately, IgM levels were not drawn given that the patient was only ill for 3 days. Based on the IgG titer (1:512) and lack of IgM data the determination of acute vs. chronic infection cannot be exactly determined.

PCR-based testing, as was done for this patient and returned positive, is more widely used to diagnose HGA than antibody tests. Indirect fluorescent antibody can be performed; however, antibodies typically become detectable 2-3 weeks after illness onset so the result was unsurprisingly negative in this case 12. For most mild to moderate B. microti infections, a 7- to 10-day treatment with oral azithromycin plus oral atovaquone is recommended. No antimicrobial therapy is suggested for asymptomatic infection. Appropriate antibiotic coverage is also necessary for coinfections, such as the 10-day doxycycline course for A. phagocytophilum in the patient case described herein.

An additional teaching point from this case arises in relation to this patient’s lab abnormalities. It has become common practice during the COVID-19 pandemic to trend D-dimers as a way of risk stratifying patients who need anticoagulation. This patient had presented with an elevated D-dimer, but had no evidence of thrombosis. Since little is known about the variation of D-dimer levels in other medical conditions (such as tick-borne illnesses), elevated levels should be interpreted with caution before initiating anticoagulation in a given clinical scenario.

4. Conclusion

Analogous to the Head-to-Toe assessment on history and physical exams - clinicians during the coronavirus pandemic should resort to broad differentials for viral complaints. Babesiosis and other tick-borne diseases can mimic COVID-19 symptoms, but appropriate history (e.g. geographical location and season) along with physical exam and laboratory findings can guide physicians on appropriate diagnosis and management. The alarming coronavirus death counts and high infectivity certainly poses a challenge, but with increased testing and public health measures, physicians should continue utilizing their pre-COVID-19 medical reasoning skills.

Declarations

Ethics approval and consent to participate.

Not applicable

Consent for Publication

Consent obtained at time of discharge.

Availability of Data and Material

Not applicable.

Competing Interests

The authors declare that they have no competing interests

Funding

Not applicable.

References

[1]  Stokes EK, Zambrano LD, Anderson KN, et al. Coronavirus Disease 2019 Case Surveillance - United States, January 22-May 30, 2020. MMWR Morb Mortal Wkly Rep. 2020; 69(24): 759-765.
In article      View Article  PubMed
 
[2]  Woloshin S, Patel N, Kesselheim AS. False Negative Tests for SARS-CoV-2 Infection - Challenges and Implications. New England Journal of Medicine. 2020; 383(6).
In article      View Article  PubMed
 
[3]  Chen L-D, Li H, Ye Y-M, et al. A COVID-19 patient with multiple negative results for PCR assays outside Wuhan, China: a case report. BMC Infectious Diseases. 2020; 20(1).
In article      View Article  PubMed
 
[4]  Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America [published correction appears in Clin Infect Dis. 2007 Oct 1; 45(7): 941]. Clin Infect Dis. 2006; 43(9): 1089-1134.
In article      View Article  PubMed
 
[5]  Swanson SJ, Neitzel D, Reed KD, et al. Coinfections acquired from ixodes ticks. Clin Microbiol Rev. 2006; 19(4): 708-727.
In article      View Article  PubMed
 
[6]  Vannier EG, Diuk-Wasser MA, Ben Mamoun C, et al. Babesiosis. Infect Dis Clin North Am. 2015; 29(2): 357-370.
In article      View Article  PubMed
 
[7]  Dahlgren FS, Heitman KN, Drexler NA, et al. Human granulocytic anaplasmosis in the United States from 2008 to 2012: a summary of national surveillance data. Am J Trop Med Hyg. 2015; 93(1): 66-72.
In article      View Article  PubMed
 
[8]  Aguero-Rosenfeld ME, Horowitz HW, Wormser GP, et al. Human granulocytic ehrlichiosis: a case series from a medical center in New York State. Ann Intern Med. 1996; 125(11): 904-908.
In article      View Article  PubMed
 
[9]  Bakken JS, Krueth J, Wilson-Nordskog C, et al. Clinical and Laboratory Characteristics of Human Granulocytic Ehrlichiosis. JAMA. 1996; 275(3): 199-205.
In article      View Article  PubMed
 
[10]  Krause PJ, Spielman A, Telford SR 3rd, et al. Persistent parasitemia after acute babesiosis. N Engl J Med. 1998; 339(3): 160-165.
In article      View Article  PubMed
 
[11]  Ruebush TK 2nd, Chisholm ES, Sulzer AJ, Healy GR. Development and persistence of antibody in persons infected with Babesia microti. Am J Trop Med Hyg. 1981; 30(1): 291-292.
In article      View Article  PubMed
 
[12]  Dawson JE, Fishbein DB, Eng TR, et al. Diagnosis of human ehrlichiosis with the indirect fluorescent antibody test: kinetics and specificity. J Infect Dis. 1990; 162(1): 91-95.
In article      View Article  PubMed
 

Published with license by Science and Education Publishing, Copyright © 2021 Amandeep S. Saini and Jacob Schwartz

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Cite this article:

Normal Style
Amandeep S. Saini, Jacob Schwartz. Differential Diagnosis in the Age of COVID-19 and the Need to Maintain a Broad Differential. American Journal of Medical Case Reports. Vol. 9, No. 1, 2021, pp 62-64. http://pubs.sciepub.com/ajmcr/9/1/15
MLA Style
Saini, Amandeep S., and Jacob Schwartz. "Differential Diagnosis in the Age of COVID-19 and the Need to Maintain a Broad Differential." American Journal of Medical Case Reports 9.1 (2021): 62-64.
APA Style
Saini, A. S. , & Schwartz, J. (2021). Differential Diagnosis in the Age of COVID-19 and the Need to Maintain a Broad Differential. American Journal of Medical Case Reports, 9(1), 62-64.
Chicago Style
Saini, Amandeep S., and Jacob Schwartz. "Differential Diagnosis in the Age of COVID-19 and the Need to Maintain a Broad Differential." American Journal of Medical Case Reports 9, no. 1 (2021): 62-64.
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[1]  Stokes EK, Zambrano LD, Anderson KN, et al. Coronavirus Disease 2019 Case Surveillance - United States, January 22-May 30, 2020. MMWR Morb Mortal Wkly Rep. 2020; 69(24): 759-765.
In article      View Article  PubMed
 
[2]  Woloshin S, Patel N, Kesselheim AS. False Negative Tests for SARS-CoV-2 Infection - Challenges and Implications. New England Journal of Medicine. 2020; 383(6).
In article      View Article  PubMed
 
[3]  Chen L-D, Li H, Ye Y-M, et al. A COVID-19 patient with multiple negative results for PCR assays outside Wuhan, China: a case report. BMC Infectious Diseases. 2020; 20(1).
In article      View Article  PubMed
 
[4]  Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America [published correction appears in Clin Infect Dis. 2007 Oct 1; 45(7): 941]. Clin Infect Dis. 2006; 43(9): 1089-1134.
In article      View Article  PubMed
 
[5]  Swanson SJ, Neitzel D, Reed KD, et al. Coinfections acquired from ixodes ticks. Clin Microbiol Rev. 2006; 19(4): 708-727.
In article      View Article  PubMed
 
[6]  Vannier EG, Diuk-Wasser MA, Ben Mamoun C, et al. Babesiosis. Infect Dis Clin North Am. 2015; 29(2): 357-370.
In article      View Article  PubMed
 
[7]  Dahlgren FS, Heitman KN, Drexler NA, et al. Human granulocytic anaplasmosis in the United States from 2008 to 2012: a summary of national surveillance data. Am J Trop Med Hyg. 2015; 93(1): 66-72.
In article      View Article  PubMed
 
[8]  Aguero-Rosenfeld ME, Horowitz HW, Wormser GP, et al. Human granulocytic ehrlichiosis: a case series from a medical center in New York State. Ann Intern Med. 1996; 125(11): 904-908.
In article      View Article  PubMed
 
[9]  Bakken JS, Krueth J, Wilson-Nordskog C, et al. Clinical and Laboratory Characteristics of Human Granulocytic Ehrlichiosis. JAMA. 1996; 275(3): 199-205.
In article      View Article  PubMed
 
[10]  Krause PJ, Spielman A, Telford SR 3rd, et al. Persistent parasitemia after acute babesiosis. N Engl J Med. 1998; 339(3): 160-165.
In article      View Article  PubMed
 
[11]  Ruebush TK 2nd, Chisholm ES, Sulzer AJ, Healy GR. Development and persistence of antibody in persons infected with Babesia microti. Am J Trop Med Hyg. 1981; 30(1): 291-292.
In article      View Article  PubMed
 
[12]  Dawson JE, Fishbein DB, Eng TR, et al. Diagnosis of human ehrlichiosis with the indirect fluorescent antibody test: kinetics and specificity. J Infect Dis. 1990; 162(1): 91-95.
In article      View Article  PubMed