# Case Report: Pulmonary Leptospirosis Misdiagnosed as COVID-19

Jean-Marie Turmel, Claude Olive, Bastien Bigeard, Sylvie Abel, Rishika Banydeen, Laura Daoud, Pierre-Marie Fayolle, André Cabié

► To cite this version:

Jean-Marie Turmel, Claude Olive, Bastien Bigeard, Sylvie Abel, Rishika Banydeen, et al.. Case Report: Pulmonary Leptospirosis Misdiagnosed as COVID-19. American Journal of Tropical Medicine and Hygiene, 2022, 107 (1), pp.97-99. 10.4269/ajtmh.21-1102. hal-03687757

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Distributed under a Creative Commons Attribution 4.0 International License
Case Report: Pulmonary Leptospirosis Misdiagnosed as COVID-19

Jean-Marie Turmel,¹* Claude Olive,² Bastien Bigeard,¹ Sylvie Abel,¹ Rishika Banydeen,³ Laura Daoud,⁴ Pierre-Marie Fayolle,⁴
André Cabié,¹ for the COVID-19 Study Group of the University Hospital of Martinique⁵

¹Department of Tropical and Infectious Diseases, Centre Hospitalier Universitaire de Martinique, Fort de France, France; ²Bacteriology Laboratory, Centre Hospitalier Universitaire de Martinique, Fort de France, France; ³Department of Clinical Research, Centre Hospitalier Universitaire de Martinique, Fort de France, France; ⁴Intensive Care Unit, Centre Hospitalier Universitaire de Martinique, Fort de France, France; ⁵Centre Hospitalier Universitaire de Martinique, Fort de France, France

**Abstract.** We report the case of an 83-year-old woman with acute, febrile respiratory failure resulting from interstitial pneumonia that required high-flow oxygen therapy. This clinical picture, associated with the ongoing epidemiological situation, initially guided us toward a diagnosis of COVID-19. Based on SARS-CoV-2 reverse transcription–polymerase chain reaction negativity and the absence of anti-SARS-CoV-2 antibodies, a search for a differential diagnosis was conducted that led us to conclude a diagnosis of severe pulmonary leptospirosis. This case highlights the need to engage in early discussions about differential diagnoses, including neglected tropical and subtropical diseases, during the COVID-19 era.

INTRODUCTION

SARS-CoV-2 infection has generated a worldwide pan-
demic since early 2020. In a pandemic situation, the propor-
tion of COVID-19 compared with other infectious diseases
increases among primary care patients. This epidemiological
trend modification can lead to diagnostic errors, in particular
when clinical, biological, or radiological similarities exist. We
report a case of severe pulmonary leptospirosis misdiag-
nosed as severe COVID-19.

CASE REPORT

In the French Caribbean island of Martinique, the second
COVID-19 pandemic wave occurred between September 1
and December 31, 2020. During this period, 290 patients
were treated in our center, a tertiary university hospital.

On December 6, 2020, an 83-year-old woman without sig-
nificant medical history presented to the emergency room
with dyspnea. The patient's symptoms appeared on Decem-
ber 2 (day 1) and included myalgia, arthralgia, and diarrhea.
Three days later, she was dyspneic and had a fever, which
led her to be admitted to our hospital.

On admission, the patient's body temperature was
38.8°C, with an oxygen saturation at ambient air of 88% and
polypnea at 40 cycles/min. The patient was dyspneic when
talking or carrying out low-level physical activity. Clinical
examination revealed bilateral crackles at the pulmonary
bases, with the absence of jaundice, rash, and conjunctival
suffusion. Her mental status was deemed normal.

Laboratory exams showed lymphopenia at 140 lympho-
cytes/mm³, thrombocytopenia at 101,000 thrombocytes/
mm³, and a serum creatinine level of 91 µmol/L (normal
value, 55 µmol/L). The patient's blood urea nitrogen level
was 11.6 mmol/L, and aspartate aminotransferase and ala-
nine aminotransferase were at 160 and 62 U/L respectively.
Her bilirubin level was normal, C-reactive protein was at
350 mg/L, and B-type natriuretic peptide was normal at
105 pg/mL (Table 1).

A first SARS-CoV-2 reverse transcription–polymerase
chain reaction (RT-PCR) test was performed on a nasopha-
ryngeal sample on day 5 of symptoms and was negative.
Influenza, respiratory syncytial virus, metapneumovirus, and
rhinovirus PCR tests were also negative, as were serum
dengue virus RT-PCR and dengue serology. Legionella pneu-
mophila (serogroup I) urinary antigen was equally absent.
Computed tomography (CT) of the chest was performed on
admission and revealed ground-glass opacities, with a distri-
bution that was bilateral and mixed: peripheral and peri-
bronchovascular. About 25% of the lung parenchyma was
affected (Figure 1).

At this stage, the suggested diagnosis was severe COVID-
19 pneumonia, with a false-negative RT-PCR. Rapidly, on
day 6, the patient's respiratory condition worsened, requiring
admission to the intensive care unit (ICU) to increase oxygen
therapy. The administered ICU treatment combined high-flow
oxygen therapy with OPTIFLOW™ (Fisher & Paykel Health-
care, Auckland, New Zealand) and corticosteroid therapy
with dexamethasone (6 mg/d). No antibiotic therapy was
introduced, based on the negativity of the initial microbiologi-
cal and CT examinations. Respiratory parameters improved
on day 8, and high-flow oxygen therapy was weaned. The
patient left the ICU on day 9 and was transferred to the infec-
tious disease ward.

Faced with the lack of microbiological documentation,
investigations were extended. SARS-CoV-2 RT-PCR tests
on a nasopharyngeal sample were repeated on days 5 and 7
after symptom onset and were again negative. Anti-SARS-
CoV-2 IgM and IgG antibody serologies performed on days
5 and 10 were equally negative.

The medical team's hunch was then to test for the presence
of leptospirosis, a tropical disease endemic to the island. Lep-
tospirosis is known to have a strong seasonality, with incident
cases expected mostly during the rainy season (the last
3 months of the year for Martinique). Leptospirosis serology
performed on day 8 with ELISA (OnSite™ Leptospira IgG/IgM
Combo Rapid Test) showed the presence of anti-Leptospira
IgMs. IgM presence was confirmed with another ELISA test
(Hurstbridge), with a titer of 1:6,400. On the same blood sam-
ple, a microagglutination test (Martin et Pettit Microagglutina-
tion test) did not, however, allow the identification of a specific
Leptospira serovar, probably because of the precocious

<footnote>*Address correspondence to Jean-Marie Turmel, Service de
Maladies Infectieuses et Tropicales, Centre Hospitalier Universitaire
de Martinique, CS 90632-97261 Fort de France Cedex, France.
E-mail: jean-marie.turmel@chu-martinique.fr</footnote>
<table><caption>TABLE 1
Patient's blood test and microbiological results during hospitalization</caption><thead><tr><th>Results</th><th>Day 5* (12/6/2020)</th><th>Day 7* (12/8/2020)</th><th>Day 8* (12/9/2020)</th><th>Day 10* (12/11/2020)</th></tr></thead><tbody><tr><td>Leukocytes (cells/mm³)</td><td>1,650</td><td>10,120</td><td>11,190</td><td>12,540</td></tr><tr><td>Neutrophils/mm³</td><td>1,490</td><td>9,150</td><td>-</td><td>-</td></tr><tr><td>Lymphocytes/mm³</td><td>140</td><td>680</td><td>-</td><td>-</td></tr><tr><td>Platelets/mm³</td><td>101,000</td><td>81,000</td><td>109,000</td><td>138,000</td></tr><tr><td>C-reactive protein (mg/L)</td><td>350.2</td><td>395.1</td><td>-</td><td>153.7</td></tr><tr><td>Creatinine (µmol/L)</td><td>91</td><td>60</td><td>-</td><td>56</td></tr><tr><td>Blood urea nitrogen (mmol/L)</td><td>11.6</td><td>7.9</td><td>-</td><td>13.3</td></tr><tr><td>Kalemia (mmol/L)</td><td>2.6</td><td>3.4</td><td>-</td><td>3.9</td></tr><tr><td>Aspartate aminotransferase (U/L)</td><td>160</td><td>61</td><td>35</td><td>-</td></tr><tr><td>Alanine aminotransferase (U/L)</td><td>62</td><td>56</td><td>41</td><td>-</td></tr><tr><td>Total Bilirubin (mmol/L)</td><td>15.9</td><td>8</td><td>12.7</td><td>13.4</td></tr><tr><td>NP SARS CoV-2 RT-PCR</td><td>Negative</td><td>Negative</td><td>-</td><td>-</td></tr><tr><td>Serum SARS CoV-2 IgG and IgM (ELISA)</td><td>Negative</td><td>-</td><td>-</td><td>Negative</td></tr><tr><td>Serum Leptospira RT-PCR</td><td>Positive</td><td>-</td><td>Negative</td><td>Negative</td></tr><tr><td>Serum Leptospira IgM (ELISA)</td><td>Negative</td><td>-</td><td>Positive</td><td>-</td></tr></tbody></table>

NP = nasopharyngeal; RT-PCR, reverse transcription-polymerase chain reaction.

timeliness of sample collection. A *Leptospira* RT-PCR test was also performed on the same day (day 8) and was negative. This RT-PCR was carried out on an Applied Biosystems™ 7500 Real-Time PCR Systems (Thermo-Fisher Scientific, Waltham, MA) using the DNA-binding dye technique (SYBR Green), with the primer set consisting of LFB1-F (5'-CATTCATGTTTCGAATCATTTCAAA-3') and LFB1-R (5'-GGCCC AAGTTCCTTCTAAAAG-3'). The entire process is detailed further by Merien et al.¹ Faced with a positive *Leptospira* serology on day 8 and a concordant clinical picture, a *Leptospira* RT-PCR test was performed retrospectively on a blood sample collected on day 5, and it turned out to be positive. On the basis of these microbiological confirmations and the patient's previous CT results, the diagnosis of leptospirosis-induced pneumonia was retained: pulmonary leptospirosis. These findings triggered the start of antibiotic therapy with amoxicillin on day 10, despite clinical improvement. Steroid therapy was continued. From then on, the patient's clinical condition improved progressively. Renal function recovered without needing hemodialysis; diuresis was always preserved. A retrospective investigation yielded

that the patient might have been exposed to *Leptospira* via rats present in her garden.

The patient was discharged from the hospital to her home on December 15, 2020, 12 days after admission. Before discharge, the patient provided informed oral consent for the use of her medical data for research purposes.

DISCUSSION

Pulmonary leptospirosis and COVID-19 pneumonia share many similarities. Those similarities in clinical presentation, combined with the ongoing COVID-19 pandemic wave at the time, led to the patient's misdiagnosis. Indeed, flu-like symptoms, acute respiratory distress, a high C-reactive protein level, and CT-identified peripheral ground-glass opacities are signs that are strongly suggestive of either one of these two diseases. As such, although leptospirosis is endemic to tropical Martinique, its diagnosis was finally evoked, only when faced with the negativity of first-intention microbiological assessments for respiratory disease. Pulmonary leptospirosis diagnosis was confirmed through the combination of two test results: a positive PCR on the day 5 blood sample, and IgM-positive ELISA serology on day 8. This thus rules out the hypothesis of a random false-positive test result. As for the negative PCR result for *Leptospira* on the day 8 blood sample, it can be explained by the known fact that leptospirosis occurs during the first acute disease stage before symptom onset, and usually lasts 7 days at most.² Leptospirosis severity was established based on the presence of the following criteria: severe respiratory failure, initial renal injury with hypokalemia, and elevation of transaminases.

Leptospirosis is a globally distributed, neglected zoonotic infection affecting mainly subtropical and tropical areas, and more rarely temperate areas. It is caused by spirochete bacteria of the genus *Leptospira*. Clinical presentation can be varied, ranging from a subclinical disease to multiple-organ failure. According to O'Neil et al.,³ pulmonary complications occur in 20% to 70% of cases. They are characterized by intra-alveolar hemorrhage and lesional pulmonary edema. The pathogenesis features leading to alveolar hemorrhage are not yet fully understood. *Leptospira* adhesion could be possible thanks to its attachment capacity to cadherins. One of the induced damage mechanisms could be toxin-

<figure><img src="image_2.png" /><figcaption>FIGURE 1. Computed tomographic chest scan at admission, 5 days after symptom onset.</figcaption></figure>

<footnote>* After symptom onset. Symptom onset (day 1) was December 2, 2020.</footnote>
mediated destruction; endotoxin activity of the outer membrane of spirochetes and production of exotoxin could lead to septal capillary injury.⁴,⁵ Another presumed mechanism is a host immune response, with elevated levels of inflammatory cytokines, as reported in patients with leptospirosis.²,⁶,⁷

Leptospirosis-linked respiratory symptoms may manifest either as mild symptoms (dyspnea, cough, hemoptysis) or immediately as acute respiratory failure. These symptoms most commonly appear in a context of fever or flu-like illness, between days 4 and 6 after disease onset.⁴,⁶ In a pulmonary leptospirosis case series by Gouveia et al.,⁸ hemoptysis was an uncommon symptom at admission (15%), whereas pulmonary hemorrhage was visible during intubation for only 40% of patients. Non-respiratory manifestations were similar between those with and without pulmonary leptospirosis. Chest radiography can be normal despite lung damage.⁹ CT is more sensitive for the detection of intralveolar hemorrhage signs. With high-resolution CT, bilateral ground-glass opacities are the most frequent abnormalities. Areas of consolidation or crazed paving patterns have also been described.⁴

Leptospira remains susceptible to many antibiotics, including beta-lactams. Penicillin or doxycycline are the first-line antibiotic therapies usually used. The benefit of antibiotic therapy is, however, controversial regarding mortality and symptom duration.¹⁰ It might only have a benefit during the early days of the disease, mainly in complicated forms. Complications of leptospirosis being partly immune mediated, anti-inflammatory agents could contribute to the treatment. Adjunctive steroid treatment has also been discussed by some authors, with the sole open-label randomized clinical trial published until now, concluding on its ineffectiveness.¹¹,¹²

The case fatality rate of pulmonary leptospirosis remains very high (> 50%). Pulmonary involvement is thus a pejorative prognostic factor of leptospirosis.⁴,⁶,⁸

## CONCLUSION

This case report raises awareness about the risk of misdiagnosis during COVID-19 pandemic phases, particularly relating to pulmonary leptospirosis. The latter's prognosis is serious, and early antibiotic administration is recommended. In the presence of an evocative clinical profile, combined with negative SARS-CoV-2 RT-PCR test, it should be sought systematically in endemic areas for leptospirosis or in travelers returning from these areas.

Received October 20, 2021. Accepted for publication March 14, 2022.

Published online May 16, 2022.

Acknowledgments: The American Society of Tropical Medicine and Hygiene has waived the open-access fee for this article due to the ongoing COVID-19 pandemic and has assisted with publication expenses.

Additional members of the COVID-19 study group of the University Hospital of Martinique include Sonia Abid, Ornella Cabras, Cyrille Chabartier, Agathe Chaplain, Georges Dos Santos, Laurence Fagour, Pauline Genieys, Emmanuelle Guerin, Diane Guilloux, Karine Guitteaud, François Javaugue, Jonas Jolivert, Cyrielle Le Nezet, Mélanie Lehoux, Athéna Marquise, Hossein Mehdaoui, Fatiha Najioullah,

Karine Pailla, Diane Paris, Sandrine Pierre-François, Dabor Resiere, Marie Sabia, Michel Schloesser, Marie Soury, Rafaelle Theodose, Ruddy Valentino, Shazima Vally, and Laurent Wolf.

Authors' addresses: Jean-Marie Turmel, Bastien Bigeard, Sylvie Abel, and André Cabié, Department of Tropical and Infectious Diseases, Centre Hospitalier Universitaire de Martinique, Fort de France, France, E-mails: jean-marie.turmel@chu-martinique.fr, bastien.bigeard@chu-martinique.fr, sylvie.abel@chu-martinique.fr, and andre.cabie@chu-martinique. Claude Olive, Bacteriology Laboratory, Centre Hospitalier Universitaire de Martinique, Fort de France, France, E-mail: claud.olive@chu-martinique.fr. Rishika Banydeen, Department of Clinical Research, Centre Hospitalier Universitaire de Martinique, Fort de France, France, E-mail: rishika.banydeen@chu-martinique.fr. Laura Daoud and Pierre-Marie Fayolle, Intensive Care Unit, Centre Hospitalier Universitaire de Martinique, Fort de France, France, E-mails: laura.daoud@chu-martinique.fr and pierre-marie.fayolle@chu-martinique.fr.

This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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