Introduction

Pneumocystosis is a potentially life-threatening respiratory tract infection, caused by Pneumocystis jirovecii, occurring almost exclusively in immunocompromised patients and especially those with HIV infection with a low CD4 count. Biologics are a novel class of drugs, commonly used in the treatment of hematological malignancies and autoimmune inflammatory diseases, such as chronic lymphocytic leukemia, rheumatoid arthritis and Crohn’s disease. With the exception of lymphocyte-depleting agents, such as the anti-CD20 monoclonal antibody Rituximab and the anti-CD52 combined T and B cell-depleting antibody Alemtuzumab, the causal relationship of biologic agents with the occurrence of PJP remains unclear. Lymphopenia and prolonged neutropenia are known risk factors for pneumocystosis. Τhe development of lymphopenia is common during treatment with these agents, predisposing to PJP. Thus, current guidelines encourage physicians to prescribe cotrimoxazole prophylaxis in patients receiving Alemtuzumab, in order to reduce the risk of pneumocystosis [1].

The blockade of TNF in patients with rheumatoid arthritis with the use of TNF inhibitors appears to be beneficial in disease control, but has been associated with an increased risk of opportunistic infections, such as pneumocystosis. Anti-TNF-a Infliximab, is a chimeric monoclonal antibody that binds to TNF-a, resulting in inhibition of its binding to lamina propria-localized mucosal cell receptors. However, inhibition of the action of TNF-a is not without hazard, as TNF-a plays a crucial role in promoting the maturation of cytokines that ensure the host's defense against pathogenic microorganisms. The main risk factors for the development of PJP in patients receiving Infliximab are advanced age, concomitant chronic lung disease, and the administration of high doses of glucocorticoids [2, 3].

On the other hand, Etanercept is a competitive inhibitor of the binding of tumor necrosis factor to its receptors on the cell surface, thus suppressing cellular responses mediated by TNF, thus, rendering it biologically inactive. As in the case of Infliximab, the main risk factors for the development of PJP among patients receiving Etanercept appear to be advanced age and chronic lung disease, while the contribution of high weekly doses of methotrexate is also important. According to Tanaka et al., the onset of pneumocystosis in patients receiving Etanercept is often characterized by an acute onset of respiratory failure, even with normal levels of lymphocytes or serum IgG [4].

In contrast to the above, a very small number of reports exist, regarding the possible correlation of anti-TNF Adalimumab with PJP. Therefore, we performed a literature search in Pubmed database, using the terms “Adalimumab and Pneumocystis” in August, 2023 and found 21 research items. Among these, six were excluded as they dealt with co-infection with Mycobacterium tuberculosis, with rheumatoid meningitis per se, while one reference was written in Japanese, one JPJ case was attributed to the use of leflunomide, one included non PJP and one last occurred in a child. Totally, out of the 21 references, 14 were included in our literature search. In addition, in Pubmed database, we used the words “cotrimoxazole and tremor” and we found 16 references, amongst which the most recent was reported in 2018 and we decided to use only this reference. Herein, we present a case of an adult female patient on adalimumab, who developed PJP.

Case presentation

A 53-year-old female patient presented to the emergency department of our hospital due to fever accompanied by dry cough and mild shortness of breathing for the last 3 days. Her past medical history was remarkable for rheumatoid arthritis, for which she was treated with methotrexate, while in the last month Adalimumab was added to the regimen. In addition, she was treated with escitalopram for depression for the past 10 years. On clinical presentation, the patient was hemodynamically stable, but had fever and mild respiratory distress with SaO2 = 91%. Routine laboratory tests revealed a mild increase in inflammatory markers and anemia, while serum LDH was elevated. Chest X-ray did not show any specific findings, so the patient underwent a high resolution computed tomography (HRCT) of the chest, which showed a ground-glass pattern (Fig. 1).

Fig. 1
figure 1

Ground-glass pattern in HRCT

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Based on the patient's medical history, the clinical manifestations and the ground-glass pattern in HRCT, PJP was suspected. Beta-d-glucan assay was positive, the values of which were particularly elevated. Based on the above, we considered the possibility of PJP infection very likely and thus decided to discontinue methotrexate and Adalimumab, while the patient received antimicrobial therapy with cotrimoxazole in combination with prednisolone. The patient gradually experienced remission of fever and dyspnea, as well as an improvement in the laboratory profile. However, she denied performing a bronchoscopy to send bronchoalveolar lavage for PJP. 5 days later, cotrimoxazole was discontinued, as the patient developed severe resting tremor in the upper extremities, as well as electrolyte disturbances, such as hyponatremia and hyperkalemia. The patient received an alternative therapy with primaquine and clindamycin, with total treatment duration of 21 days and was discharged from the hospital in a good clinical condition (Table 1).

Table 1 Clinical and laboratory findings on admission and revaluation, respectively
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Discussion

Pneumocystis jirovecii, formerly known as Pneumocystis carinii, is a yeast-like fungus of the genus Pneumocystis, causally associated with the occurrence of pneumonia. Transmission is mainly achieved by the airborne route by person-to-person spread. The main reservoirs of carriers are asymptomatic immunocompetent individuals, where usually PJP replicates within the respiratory alveoli. The main risk factors for PJP are HIV infection, malignancy, transplantation and the administration of specific drugs. Patients with granulomatosis with polyangiitis, treated with prednisolone and cyclophosphamide, are at increased risk, as well as patients receiving Alemtuzumab [5,6,7,8]. Main drugs associated with increased risk of PCP infection are listed in Table 2.

Table 2 Main drugs associated with increased risk for PJP
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The use of biologic agents in the treatment of autoimmune diseases and hematological malignancies is now widespread, with the main disadvantage of their administration being the increased risk of opportunistic infections. Despite the fact that the administration of specific biologic agents, such as Alemtuzumab and Infliximab, is causally related to the occurrence of PJP, for other agents the available data are limited. Proposed risk factors for the development of pneumocystosis in patients treated with biologics are advanced age, history of chronic lung disease, lymphopenia, hypoalbuminemia, and concomitant administration of high-dose of glucocorticoids or weekly methotrexate.

Adalimumab is a relatively recent recombinant human IgG1 antibody, with increasing use in rheumatoid arthritis, due to its ability to exert anti-inflammatory activity through binding to TNF. The association of the drug with the occurrence of PJP remains unclear, as only few case reports have been reported. Watanabe et al. investigated the clinical characteristics and risk factors of PJP among 17 patients with RA treated with Adalimumab and showed that PJP may occur early in the course of Adalimumab therapy in patients with RA. The median time to onset of Adalimumab-induced PJP was 12 weeks, and the median age at diagnosis being 68 years old [8].

The major clinical manifestations of PJP are fever, dyspnea and cough, although the clinical expression of the disease differs between HIV and non-HIV patients. In patients without a history of HIV infection, respiratory tract injury usually manifests as acute respiratory failure with fever and nonproductive cough. On the contrary, in HIV patients, the clinical expression of the infection is usually more progressive over days to weeks, while fatigue, chest pain or even weight loss may coexist. The patient typically exhibits hypoxemia on exercise, whereas in severe disease, the patient may also experience extrapulmonary manifestations. Laboratory findings are nonspecific, although a significant percentage of patients have lymphopenia and elevated serum LDH. In addition, an increase in serum beta-D-glucan can be seen, as a result of its presence in the cell wall of P.jirovecii.

High-resolution computed tomography may reveal a variety of pathological patterns, with bilateral diffuse interstitial infiltrates, particularly in non-HIV patients, being the most common finding. Alternatively, nodular ground-glass opacities may be seen, as well as nodules, cysts and lobular infiltrates. Pneumothorax is a severe complication of PJP, whereas cavitation and pleural effusions are typically absent. Staining and polymerase chain reaction (PCR) in induced sputum or bronchoalveolar lavage (BAL) specimens is the first step in making the diagnosis. Positive test rates are usually higher in HIV patients, due to a higher burden of the infection. If the above specimens cannot be collected safely, treatment may be given based in the presence of risk factors in combination with compatible clinical and radiological findings and elevated serum beta-d-glucan [9,10,11,12,13,14].

Cotrimoxazole is the gold standard of treatment with the major drawback its ability to cause systemic toxicity. Cotrimoxazole is an antibiotic agent active against a wide variety of aerobic Gram-positive and Gram-negative bacteria, while at the same time remains the treatment of choice in non-bacterial infections, such as toxoplasmosis and PJP. It consists of trimethoprim and sulfamethoxazole in a ratio of 1:5, with bactericidal action, attributed to the trimethoprim component. Electrolyte disturbances are not uncommon during therapy, in contrast with tremor which is an unusual side effect. Possible mechanisms involved in the occurrence of hyponatremia include the induction of a SIADH-like syndrome, as well as the diuretic effect induced by trimethoprim, which exhibits an amiloride-like effect. This effect of trimethoprim seems to be also responsible for the occurrence of hyperkalemia, through inhibition of epithelial sodium channels in the distal nephron.

On the other hand, cotrimoxazole-induced neurotoxicity appears to be dose-dependent, usually occurring within 2–8 days of drug initiation and resolves in a period of 3–10 days after cotrimoxazole discontinuation. The mechanism by which cotrimoxazole promotes neurotoxicity is unknown, although it may be attributed to the inhibition of phenylalanine metabolism, as well as to the reduction of concentrations of tetra-hydrobiopterin, which in turn contributes to the increased production of serotonin and catecholamines [15].

In patients unable to receive cotrimoxazole, as in our case, alternative treatment options include the combination of primaquine with clindamycin and pentamidine. In mild to moderate PJP, atovaquone is considered as a second-line therapy. Supplementary administration of glucocorticoids is recommended in all patients with HIV and moderate or severe PJP and in selected patients without HIV. The main indications for adjunctive administration of glucocorticoids in non-HIV patients are the presence of room air oxygen saturation (SaO2) < 92% or a partial pressure of oxygen (PaO2) < 70 mm Hg or an alveolar-arterial (A-a) oxygen gradient ≥ 35 mmHg. The total duration of therapy of PJP is 21 days.

Patients receiving immunomodulatory therapy are at increased risk for opportunistic infections, such as PJP. Even though Adalimumab is not an established risk factor for pneumocystosis, recently a few number of cases have shown a possible correlation of its use with the occurrence of pneumonia due to P.jirovecii. The more frequent use of Adalimumab in the treatment of autoimmune diseases may trigger new cases of P.jirovecii infection in the near future. In this context, Adalimumab may be added to the list of established risk factors for PJP, especially among patients with a history of recent initiation of the drug, in the absence of other known predisposing factors. Nevertheless, risk stratification is essential, based mainly on the number of immunoregulatory agents and the degree of immunosuppression. Therefore, a potential utility of cotrimoxazole prophylaxis in selected cases of severe immunosuppression may be beneficial.

A limitation of the study is that it is only a case report. However, the presentation of our case may have an additive value to the existing limited data. The rising number of reports may shed light on this debatable issue, resulting in changes in the management of patients receiving Adalimumab.

Conclusion

Despite the fact that adalimumab has not been officially appointed as a risk factor for PJP to the extent that chemoprophylaxis with cotrimoxazole should be added to the patient’s regimen, more long-term studies are needed to further elucidate that issue. In conclusion, clinicians should bear in mind the possibility of PJP among patients receiving adalimumab, as the correct and timing diagnosis may be really life-saving.