Misdiagnosis of pneumorrhagia leptospirosis as common CAP: A case report and literature review

Abstract

Background

The incidence of critical leptospirosis manifested as massive pulmonary hemorrhage has been significantly reduced, which has been rarely reported in recent years, while the mortality rate is extremely high once it occurs.

Case presentation

A 54-year-old man with no HIV infection was admitted to the local county hospital due to high-grade continuous fever lasting four days (38.5–40.5C), upper limb and shoulder-back muscle pain, and general fatigue. The chest CT (Aug 26, 2021) showed “multiple patchy, cloudy, and fuzzy shadows in both lungs, mainly under the pleura of the upper and lower lobes of both lungs; some lymph nodes in the mediastinum are enlarged”. Despite being diagnosed with “common community-acquired pneumonia” and starting injectable levofloxacin, the symptoms worsened, and massive hemoptysis occurred. However, after being transferred to our hospital, the patient was diagnosed with the “pulmonary hemorrhage type of leptospirosis” through comprehensive dynamic analysis. The patient recovered very well after undergoing “penicillin 3MIU q6h” alone for two weeks to fight the infection.

Conclusions

Leptospirosis has a high mortality rate when it becomes critical or severe. Diagnosis typically relies on factors such as epidemiology, clinical symptoms, and pathogenetic testing. Metagenomic next-generation sequencing (mNGS) is more effective in sensitivity and speed than traditional detection methods, making it an excellent option for diagnosing challenging and severe infections in emergencies. Additionally, when experiencing sudden coughing up of blood, it's important to consider the possibility of pulmonary hemorrhage as a type of leptospirosis.

1. Background

Leptospirosis is an infectious disease caused by various serotypes of Leptospira, which is transmitted by contact with urine, water, or soil contaminated with urine from animal reservoirs such as rodents, dogs, and livestock [1]. It is commonly known as “rice blast”, "Weil's disease” or “swine fever” and is primarily associated with activities related to agriculture, sanitation, and animal husbandry. It is considered the most widespread zoonosis in the world and has a global distribution, with a higher incidence in the tropics and subtropics [2]. The number of human cases per 100,000 individuals ranges from 10 to 100 [3,4]. Most patients with leptospirosis infection are mild or asymptomatic. However, 5–10 % of symptomatic patients develop critically jaundiced leptospirosis. Prevention efforts have decreased the incidence of critical leptospirosis, which manifests as massive pulmonary hemorrhage, and hepatic and renal failure, in recent years [5]. It is rarely reported in China [6]. Nevertheless, this rapidly progressive multisystem disease has a mortality rate ranging from 9 % to 31 %, even under intensive care unit (ICU) monitoring [[7], [8], [9]] [[7], [8], [9]] [[7], [8], [9]].

This paper aims to enhance the knowledge of clinical workers on critical pulmonary hemorrhagic leptospirosis. By providing a case study, it emphasizes the importance of early diagnosis and treatment to decrease the occurrence of mild to severe disease progression and mortality rates for critically ill patients.

2. Case presentation

A male patient, aged 54 and residing in southwest China's Chongqing, sought medical attention at our hospital on August 28, 2021. He was in good health four days before admission but developed a high-grade continuous fever (38.5–40.5°C) with chills, accompanied by upper limb and shoulder-back muscle pain, and fatigue. The fever partially subsided after taking oral antipyretics. There were no other symptoms such as cough, sigh, runny nose, headache, abdominal pain, diarrhea, or vomiting. He was diagnosed with “common community-acquired pneumonia (CAP)" at a local hospital after a chest CT scan (Aug 26, 2021) showed multiple patchy shadows in both lungs. He was prescribed injectable levofloxacin (0.5 g intravenous once daily) for broad-spectrum coverage of possible atypical and common community-acquired pathogens, but his symptoms worsened, causing him to experience massive hemoptysis. Consequently, he was referred to our hospital's Department of Respiratory and Critical Care Medicine at the First Affiliated Hospital of Army Medical University for further treatment. The patient had a history of trimming pig pens and cleaning pig manure two days before the onset of his illness, along with a smoking history of more than 40 pack years and occasional drinking. He also mentioned harvesting rice in the field two weeks before the onset of symptoms. There was no significant family history.

During the physical examination for admission, the patient had a pulse rate of 92 beats per minute, respiration rate of 20 times per minute, and blood pressure of 150/93 mmHg. The blood oxygen saturation was at 87 % without oxygen. The patient's breathing was slightly faster and there was weakened left respiratory motility. There was also an increase in left speech fibrillation. Thick respiratory sounds were detected in both lungs and fine wet rales were heard in the left lung. However, the rest of the examination showed normal results.

Upon admission, the patient's blood gas analysis indicated that they were experiencing type I respiratory failure. A chest-abdominal CT was conducted on August 28, 2021, which revealed enlarged and disorganized pulmonary blood vessels and bronchial bundles, thickened lobular septa, multiple small sack-like translucent areas in both lungs, and scattered flocculations in both lungs. Additionally, a small amount of pericardial effusion and pelvic fluid were noted. The patient's routine blood work showed elevated levels of WBC, Neu%, PCT, D-dimer, NTproBNP, ESR, TNFα, and IgE. While liver function aminotransferase and creatine kinase were mildly abnormal, respiratory virus, torch test (IgM), tuberculosis, fungus-related test, and IgG4 were normal. Autoantibody spectrum results revealed weakly positive anti-Ro52 antibody↑, weakly positive anti-mitochondrial M2 antibody↑, weakly positive tissue transglutaminase↑, and weakly positive anti-parietal cell antibody↑. In contrast, the ANCA, ANCA spectrum, ANA, and anti-glomerular basement membrane antibodies were negative. Given the extent of the patient's lung lesions had significantly increased since the previous period, the inefficacy of prior anti-infective treatment, and the heightened inflammatory indices, the patient received meropenem (1g Q8H) and moxifloxacin (0.4g QD) as a means of anti-infective, symptomatic, and supportive treatment. Concurrently, blood mNGS was promptly conducted on August 28, 2021, which revealed (August 29, 2021) Leptospira kidney, sequence number 6, with a confidence level of 99 %.

Based on the patient's symptoms, medical history, and imaging tests, a diagnosis of “pulmonary hemorrhage type of leptospirosis” was made. We adjusted the treatment plan to include only penicillin 3MIU q6h on August 29. As of August 30, the lung lesions have slightly decreased in size according to the chest CT scan. By September 10, the chest CT scan showed that the lung lesions were almost completely absorbed (Fig. 1), and decrease in venous blood inflammatory markers (Table 1).

Fig. 1.

Thorax CT scan at different time points displayed the evolution of lesions. At the onset, chest CT showed a thickening of bilateral lung markings. b At admission, development and evolution of lung lesions. The lung CT scan showed that the pulmonary blood vessels and bronchial bundles were increased and disordered, part of the lobular septa thickened, multiple small sac-like light-transmitting areas were seen in both lungs, and multiple floccules scattered in both lungs; a small amount of pericardial effusion; A small amount of fluid in the pelvis. c After treatment with Meropenem (1g Q8h) + Moxifloxacin (0.4g QD) + Penicillin (3MIU Q6h), a thorax CT scan showed bilateral lung lesions were slightly absorbed and new pleural effusion was found. d After 11 days of treatment with Penicillin (3MIU Q6h) alone, thorax CT scan showed obvious absorbance of the lung lesion.

Table 1.

Hematology detection indicators on admission and days later.

Items	Aug 28 (on admission)	Aug 31	Sep 3	Sep 10	Reference range
White blood cells (*109/L)	11.86	11.08	13.33	11.77	3.5–9.5
Neutrophils (*109/L) (%)	9.54 (80.4 %)	7.42 (67 %)	10.21 (76.6 %)	8.78 (74.6 %)	1.8–6.3 (40–75 %)
Lymphocytes (*109/L) (%)	0.73 (6.2 %)	2.01 (18.1 %)	1.76 (13.2 %)	1.89 (16.1 %)	1.8–6.3 (40–75 %)
Monocyte (*109/L) (%)	1.46 (12.3 %)	1.2 (10.8 %)	1.08 (8.1 %)	0.84 (7.1 %)	1.1–3.2 (20–50 %)
Eosinophils (*109/L) (%)	0.12 (1 %)	0.41 (3.7 %)	0.24 (1.8 %)	0.16 (1.4 %)	0.02–0.52 (0.4–8 %)
Platelet (PLT) (*109/L)	176	265	385	327	125∼350
Erythrocyte (RBC) (*1012/L)	3.19	3.51	3.25	3.83	4.3–5.8
Glutamic-pyruvic transaminase (ALT) (U/L)	54.3	89.4	37.9	19.8	13∼69
Glutamic-oxaloacetic transaminase (AST) (U/L)	27	38.8	13.1	10.3	15∼46
Glutamyl transaminase (GGT) (U/L)	380.4	329.2	214.4	163.8	12∼58
Urea (mmol/L)	4.96	6.14	5.57	8.14	3.2–7.1
Creatinine (umol/L)	85.03	53.6	59	67.1	58∼110
Creatine kinase (CK) (U/L)	44.6	169.1	44.3	33.5	55∼170
Lactic dehydrogenase (LDH) (U/L)	750.28	320.6	277.7	194.8	313∼618
Procalcitonin (PCT) (mg/ml)	4.44	1.03	0.19	0.02	0∼0.05
Erythrocyte sedimentation rate (ESR) (mm/h)	56	72	48	22	0∼20
C-reactive protein (CRP) (mg/L)	102	67.6	31.3	6.32	0∼7.44
NTproBNP (pg/ml)	6331	556.6	221.4	69.09	＜900
K+(mmol/L)	3.18	3.76	4.15	4.13	3.5–5.1
Na+(mmol/L)	141	128.2	136.6	136.5	137∼145
D2 polymer (mg/L(FEU))	1.55	1.63	0.99	0.45	0∼0.55
Blood mNGS	(Aug 29) Leptospira kidney, sequence number 6, with a confidence level of 99 %.
Fecal insect eggs	–	Negative	–	–
Blood cultures	–	–	Negative	–

3. Discussion

Leptospirosis is widespread throughout the world, especially in tropical or subtropical regions [2]. In China, most provinces, municipalities, and autonomous regions are affected by the disease [6]. However, the reporting of leptospirosis cases is often inaccurate, making it difficult to obtain reliable global incidence data. Based on a systematic review and modeling analysis, it is estimated that over one million human cases occur worldwide each year, resulting in approximately 60,000 deaths [10,11]. Cases occur throughout the year, but the peak incidence is from July to December, and the single-peak type with the epidemic peak in September is the main type of seasonal distribution of leptospirosis in China [12]. The disease mainly affects farmers and people living in poor housing conditions who have been exposed to contaminated water or the urine/blood of infected animals within 1–30 days before the onset of the disease [13].

Leptospirosis is a disease that begins suddenly with toxic blood symptoms, including three symptoms (fever, body aches, and fatigue) and three signs (conjunctival congestion, gastrocnemius muscle tenderness, and generalized superficial lymph node enlargement) [[14], [15], [16]] [[14], [15], [16]] [[14], [15], [16]]. In the intermediate stage, patients may experience pulmonary hemorrhage, myocarditis, anemia, jaundice, bleeding problems, nephritis, meningitis, respiratory and cardiac failure, and damage to other organs. Most people recover from the disease in the late stages, but a few may develop post-infection allergies such as post-fever, ocular uveitis, and cerebral artery occlusive disease. Diffuse pulmonary hemorrhage, myocarditis, and hepatorenal failure are common causes of death [15,17,18]. Target organ injury can be categorized based on clinical symptoms into several types, including influenza typhoid, pulmonary hemorrhage (both diffuse and non-diffuse), jaundice hemorrhage, renal failure, and meningoencephalitis. Diffuse pulmonary hemorrhage is a serious complication of Weil's disease. This manifestation occurs in less than 5 % of patients, with a reported mortality rate of up to 50–70 % [19].

During the acute phase of leptospirosis, laboratory results may show neutrophilia, but the total white blood cell count can be normal, reduced, or increased [20]. The outer membrane protein of Leptospira can disrupt the Na⁺-K⁺-Cl^- cotransporter in the thick segment of the ascending branch of the medullary loop, leading to imbalances in blood sodium and potassium levels [21,22]. Urinalysis of affected patients may reveal positive results for proteinuria, granular casts, and urinary occult blood. Erythrocyte sedimentation rate (ESR) is typically elevated, and approximately 50 % of patients show an increase in creatine kinase, while about 40 % have mild to moderate elevated liver transaminase [23,24]. The patient in this case had slightly elevated levels of creatine kinase and hepatic transaminase. When Leptospira enters the human body, it can enter the bloodstream through the lymphatic system or directly. Leptospira with high virulence and pathogenicity can quickly enter the pulmonary circulation, causing hypersensitivity reactions and releasing toxins that damage the pulmonary capillaries. This can result in pulmonary hemorrhage, renal hemorrhage, conjunctival congestion, uveitis, and vasculitis. Chest radiographs may show small nodules that can progress to consolidation or ground-glass opacities. Pathologically, this can represent alveolar hemorrhage, acute respiratory distress syndrome (ARDS), or pulmonary edema [25,26]. As bleeding increases, small punctate shadows can fuse and enlarge, forming patchy and even plaque shadows with blurred edges. Ground glass shadow can also form when the bleeding area is slightly larger. The distribution of lesions on chest CT after Leptospira invasion is related to the blood supply, with the outer band having more lesions than the inner band, and the dorsal side having more lesions than the anterior chest [27]. This suggests that subpleural lymphatic vessels are abundant and dorsal bleeding is related to gravity. This case supports these imaging features. However, these laboratory tests are often non-specific.

Usually, leptospirosis diagnosis is confirmed through molecular testing (polymerase chain reaction, PCR), serologic detection of leptospirosis antibody titers, pathogenic cultures, or traditional MAT serology. These methods require at least one week after symptoms appear to have high sensitivity in detecting the infection [[28], [29], [30], [31]] [[28], [29], [30], [31]] [[28], [29], [30], [31]]. In 2004, a study in India looked at 60 patients who had leptospirosis and needed intensive care unit (ICU) treatment. The study found that 77 % of these patients had multiple organ failure (MOF) and the mortality rate was high, at 52 % [7]. In Peru in 2005, a study showed that out of 321 patients with leptospirosis, 3.7 % had severe pulmonary symptoms, and 71 % of them died. The causes of death included pulmonary hemorrhage, ARDS, and MODS [19]. These studies highlight how serious leptospirosis can be. However, by detecting the disease early and getting treatment quickly, the risk of developing severe symptoms can be reduced. mNGS is a modern method of detecting pathogenic microorganisms in clinical samples. Unlike traditional methods, it doesn't rely on microbial culture or specific amplification. Instead, it uses DNA or RNA sequencing and compares it with a database to identify the types of microorganisms present in the sample. This approach is more sensitive, specific, timely, and informative than traditional methods. It can quickly and impartially detect a range of pathogenic microorganisms, including viruses, bacteria, fungi, and parasites. This makes it suitable for diagnosing severe and difficult infections in emergencies [32]. Treatment for adults with critical leptospirosis typically involves penicillin (1.5–3 million U every 6 hours), doxycycline (100mg once or twice daily), ceftriaxone (1–2g once daily), or cefotaxime (1g every 6 hours) for a 7-day course of treatment. The dosage may be adjusted for children, and pregnant women may receive penicillin, ceftriaxone, cefotaxime, or azithromycin. Leptospira infection may cause hypersensitivity and vasculitis, especially in cases involving the lungs. The jarisch-Herxheimer reaction may occur after antibiotic treatment. Some experts suggest using glucocorticoids alongside antibiotics, but there is currently not enough evidence to support this as a routine treatment [[33], [34], [35]] [[33], [34], [35]] [[33], [34], [35]]. Based on the epidemiologic history, clinical manifestations, and blood mNGS, the typical case in this paper took one day from admission to definitive diagnosis, then was treated with high-dose penicillin alone for 2 days, with marked improvement of symptoms and reduction of pulmonary lesions.

4. Conclusions

To summarize, although leptospirosis is currently not commonly seen in clinics, the mortality rate for critical and severe cases is very high. The disease has atypical clinical features, low specificity in routine laboratory tests, and a longer time for pathogenetic tests. This may lead to misdiagnosis or delayed diagnosis and treatment, resulting in a poorer prognosis and a higher mortality rate for the patient. However, using mNGS for diagnosis can greatly improve sensitivity and timeliness, making it suitable for diagnosing severe and difficult infections in emergencies. It is also important to consider the patient's clinical history in the diagnosis process. In cases of acute hemoptysis, clinicians should be knowledgeable about the differential diagnosis of pulmonary hemorrhage type of leptospirosis, to diagnose and treat early and reduce the incidence and mortality of critical leptospirosis.

Ethics approval and consent to participate

This study was reviewed and approved by the ethics committee of the First Affiliated Hospital of Third Military Medical University. Informed consent was obtained from this patient by the Declaration of Helsinki.

Consent for publication

Informed consent for their data to be used for research or publication was obtained from this patient.

Funding

Not applicable.

Data availability statement

The raw data of this article will be made available by the corresponding author (email: hqgsunshine@163.com), without undue reservation.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.